Review

The Role of Macrocyclic Compounds as Supramolecular Drug Delivery Systems:

A-Review

Muhammad Furqon Novryan Saputra¹, Yesi Nursofia², Indra Lasmana Tarigan^1,3

^1,3Department of Chemistry, Faculty of Science and Technology, Universitas Jambi, Indonesia

²College of Pharmacy, Taipe Medical University, Taiwan

³The University Center of Excellences, E2-KOLIM, Universitas Jambi

Abstract

In recent decades, significant advances in the development of drug delivery systems have unlocked new

possibilities for enhancing therapeutic efficacy. Among the diverse range of innovative materials,

macrocyclic-based supramolecular systems have emerged as promising platforms due to their unique

physicochemical properties. Macrocyclic compounds such as cyclodextrins and cucurbiturils exhibit a

remarkable ability to form stable inclusion complexes with various drug molecules, thereby improving

their solubility, chemical stability, bioavailability, and pharmacokinetic profiles. This review highlights the

design principles, synthetic strategies, and mechanisms of action underlying macrocyclic drug carriers,

with particular emphasis on their responsiveness to environmental stimuli such as pH, temperature, and

biomolecular triggers. Recent findings demonstrate that macrocyclic systems can significantly enhance

drug loading efficiency, targeted delivery, and cellular uptake, while minimizing systemic toxicity. These

advances underscore the potential of macrocyclic supramolecules as foundational elements for the

development of next-generation drug delivery systems that are more precise, effective, and adaptable

to personalized therapeutic needs.

Keywords: Drug delivery, macrocyclic, supramolecules

Graphical Abstract

Introduction

*

Corresponding author

Email addresses: indratarigan@unja.ac.id

DOI: https://doi.org/10.22437/chp.v9i1.41724

Received February 11^th2025; Accepted June 27^th2025; Available online June 30^th2025

(https://creativecommons.org/licenses/by/4.0 )

141

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Supramolecular chemistry is a branch of science

that focuses on non-covalent interactions such as

Methods

This journal review limits the discussion to

macrocyclic compounds such as cyclodextrins

(CDs), crown ethers (CE), cucurbit[n]urils (CB[n]s),

calix[n]arenes (C[n]As) and pillar[n]arene (P[n]A).

This journal review was conducted through a

systematic process comprising several stages.

First, various references related to macrocyclic

supramolecules in drug delivery systems were

comprehensively collected. Second, relevant

literature was screened and selected based on its

significance to the predetermined topic. Third,

the content of the selected publications was

hydrogen

bonding,

π-π

interactions,

and

electrostatic forces, which are used to form

complex structures with specific functions [1,2].

In the pharmaceutical field, supramolecular

approaches have shown great potential to

improve the efficiency and selectivity of drug

delivery systems [3-5]. The development of

modern drug delivery systems has become a

major focus in pharmaceutical research to

improve therapeutic efficiency and minimize side

effects. One innovative strategy that has gained

widespread attention is the utilization of host-

guest complex inclusion-based materials [2,3].

critically

understanding of recent advances in the

application of macrocyclic supramolecular

compounds as drug delivery systems.

reviewed

to

gain

an

in-depth

Supramolecular

materials

offer

various

advantages, such as high stability, structural

customizability, and large loading capacity,

making supramolecular-based materials an

excellent platform for smart drug delivery

systems [5].

The

selection

criteria

included

literature

containing the keywords: cyclodextrin, crown

ethers, cucurbit[n]urils, calix[n]arenes, and

pillar[n]arenes, while excluding studies on

compounds lacking host-guest properties and

complex binding interactions. The initial search

yielded 150 articles, which were subsequently

screened to obtain 105 eligible publications and

included 50 articles.

Among the various supramolecular systems,

macrocyclic compounds have emerged as

particularly attractive candidates for drug

delivery applications [6]. Macrocyclic compounds

are currently quite popular in drug delivery

applications. Cyclodextrins (CDs), crown ethers

(CEs), cucurbit[n]urils (CB[n]s), calix[n]arenes

(C[n]As), and pillar[n]arenes (P[n]As) are some of

the further developments in the exploration of

macrocyclic compounds as drug delivery agents

[4]. Specifically, macrocyclic compounds have

complex cavity systems that can accommodate

various

types

of

guest

molecules

[5].

Supramolecular-based drug delivery systems

(SDDS) with macrocycles are based on dynamic

“host-guest” interactions that can have reversible

changes in structure, morphology and function

[6-7]. This is very beneficial for targeted and

controlled drug release, which can reduce

damage to normal tissues or cells and improve

Figure 1. Flow diagram of review study.

diagnostic

and

therapeutic

effects.

Supramolecular interactions, such as hydrogen

bonding and π-π interactions, play an important

role in various aspects of drug delivery, including

The literature analyzed in this review was

sourced from reputable scientific journals and

publishers, including Nature, ScienceDirect, ACS

Publications, MDPI, SciELO, RSC Publishing,

AACR, PNAS, PMC Europe, ASCO, Wiley,

Chemistry Europe, and SpringerLink.

biocompatibility,

drug

loading,

stability,

targeting, and controlled release [7-8]. In

addition, the use of macrocyclics as host

molecules can

142

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

This review specifically focuses on macrocyclic

compounds such as cyclodextrins (CDs), crown

molecular

dimensions,

polarities,

and

conformations. In addition to native forms, a

plethora of chemically modified derivatives—

ethers

(CEs),

cucurbit[n]urils

(CB[n]s),

calix[n]arenes

(P[n]As), limiting the scope to their structural

characteristics, host-guest interactions, and

(C[n]As), and pillar[n]arenes

such

methylated CDs—have been developed to

further optimize solubility, complexation

as

hydroxypropyl-β-cyclodextrin

and

potential

for

drug

delivery

applications.

efficiency, and biocompatibility [10-11].

keywords. The flow diagram is shown in figure 1.

The amphiphilic nature of CDs confers a suite of

pharmaceutical advantages. The hydrophobic

cavity facilitates non-covalent encapsulation of

poorly water-soluble bioactive compounds

through van der Waals forces and hydrophobic

interactions, thereby substantially enhancing

their apparent aqueous solubility, chemical

stability, and dissolution rate. Simultaneously,

the hydrophilic outer surface promotes favorable

dispersion and wettability in biological media,

improving formulation performance [9,12].

Result and Discussion

Cyclodextrin (CD)-based SDDS

Cyclodextrins (CDs) constitute a prominent class

of macrocyclic oligosaccharides that have

garnered substantial attention as versatile

supramolecular carriers in advanced drug

delivery systems [9-10]. Structurally, CDs are

toroidal

(truncated

cone-shaped)

cyclic

oligomers, each comprising D-glucopyranose

units linked via α-1,4-glycosidic bonds. This

distinctive molecular architecture gives rise to a

hydrophobic internal cavity juxtaposed with a

hydrophilic external surface, a duality that

underpins their remarkable host–guest inclusion

capabilities (Figure 2).

Beyond solubilization, cyclodextrin inclusion

complexes can shield labile or photosensitive

drugs from environmental degradation, mitigate

undesirable organoleptic properties (e.g., bitter

taste or odor), and enable controlled or sustained

release profiles. Such multifaceted benefits

contribute

to

improved

pharmacokinetic

Among

the

naturally

occurring

CDs,

α-

predictability, enhanced bioavailability, and

potentially superior therapeutic outcomes.

Consequently,

indispensable

technologies in contemporary pharmaceutical

science and nanomedicine [12-16].

cyclodextrin, β-cyclodextrin, and γ-cyclodextrin,

containing six, seven, and eight glucose residues

respectively (Table 1), are the most extensively

characterized. Each variant exhibits a unique

cavity diameter, which dictates the selectivity and

affinity toward guest molecules of diverse

CDs

have

emerged

as

excipients

and enabling

Figure 2. Molecular structure of α-, β-, γ-CDs [11] (Reprinted with permission)

In

addition

to

improving

solubility

and

functionalized or conjugated with targeting

ligands, polymers, or other responsive moieties

to develop advanced delivery platforms capable

of site-specific drug release or stimuli-responsive

bioavailability, CDs have been employed to

reduce local irritation and systemic toxicity by

limiting direct drug interaction with biological

membranes.

Furthermore,

CDs

can

be

behavior.

For

example,

hydroxypropyl-β-

143

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

cyclodextrin and sulfobutyl ether-β-cyclodextrin

are widely used derivatives approved in various

parenteral formulations due to their favorable

safety profiles and superior solubilizing capacity.

vehicles, offering opportunities to address

challenges associated with the formulation of

hydrophobic drugs, improve therapeutic efficacy,

and enable the development of innovative

dosage forms with controlled or targeted delivery

properties [17-18].

Overall,

cyclodextrins

exhibit

remarkable

versatility as supramolecular drug delivery

Table 1. Physical properties of CDs [7]

Properties

Empirical formulas

Glucose unit total

Molecular weight (g/mol)

Inner diameter (A)

Sec. Inner (B)

α-CD

β-CD

γ-CD

C₄₈H₈₀O₄₀

8

C₃₆H₆₀O₃₀C₄₂H₇₀O₃₅

6

972

7

1135

5.8 Å

7.8 Å

15.3 Å

7.8 Å

262 Å³

18.4

1297

7.4 Å

9.5 Å

16.9 Å

7.8 Å

427 Å³

249.2

267

4.4 Å

5.7 Å

13.7 Å

7.8 Å

174 Å³

129.5

278

Outer diameter (C)

Height (h)

Capacity

Aqueous solubility (g/L)

Temperature of degradation (ºC)

298

Table 2. Comparison of cyclodextrin-based drug delivery

Types

Drugs

(Guest)

Studies

Findings

Ref.

2-hydroxypropyl-β-

cyclodextrin

(HP-β-CD)

Budesonide

(BUD)

In vitro release assay The

developed

significantly

regular improved the solubility of

[12]

using

membrane formulation

with

model

intervals from 30 min budesonide, which in turn

until 48 h, then drug contributed to enhanced

content was monitored bioavailability

and

by HPLC

therapeutic effectiveness

in managing ulcerative

colitis.

sulfobutylether—

cyclodextrin

(SBE-β-CD)

Resveratrol

(RSV) /

solfobutyl

In vitro, MTT assay was The improved formulation

conducted to evaluate led to a significant increase

[13]

[14]

the cytotoxic activity of in

RSV integrated to SBE- resveratrol,

the

solubility

of

which

β-CD

subsequently enhanced its

anticancer efficacy.

CPT-PEG-α-CD

(Cyclodextrin)

Camptothechin

(CPT)

In vitro release study of Control

drug

release,

5-FU-loaded CPT-PEG temperature- responsive,

hydrogels in PBS at improved

37ꢀ°C; drug release and

bioavailability

significant

quantified by HPLC temperature-dependent

with UV detection (265 properties for anticancer

nm for 5-FU, 372 nm activity.

for CPT-PEG).

Hydroxypropyl-β-

cyclodextrin

(HPCD)

Meropenem

(MP)

In vitro release study Improved solubility and

[15]

using

dialysis stability

solution

in

aqueous

144

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs

(Guest)

Studies

Findings

Ref.

membrane

then

monitored by UV-Vis.

Mannose-modified

γ-cyclodextrin

(M-ϒ-CD)

Regorafenib

(RG)

Comprehensive study RG@M-γ-CD nanoparticles

including in vitro drug suppressed inflammation

[16]

release,

cytotoxicity

against CT26, HT29, anti-tumor

SW480, and RKO cells; optimized

MTT and

assays improved

TAM

activation,

Regorafenib’s

effects,

in

Balb/c and C57BL/6 remodeled

tumor-bearing mice; microenvironment,

expression showing efficacy in CRC

ex vivo models.

western

and

vivo

efficacy in pharmacokinetics,

and

tumor

the

gene

analysis,

evaluations,

blotting,

histological

assessments.

In vitro drug release in Enhanced drug release,

phosphate buffer; in and formulation by

vivo acute toxicity hydrogel-delivered

Hydroxypropyl- β- Dexibuprofen

Cyclodextrin

(HP-β-CD)

[17]

evaluation using Wistar

albino rats.

Β-cyclodextrin-

Carboxymethyl

chitosan

Docetaxel

(DTX)

In vitro drug release in Improved water solubility

buffer system; in vivo of docetaxel up to 14 times

acute toxicity studies

[18]

[19]

(β-CD-CMC)

using Wistar rats.

γ-cyclodextrin

metal-organic

frameworks

(CD-MOFs)

Paeonol

(PAE)

In

phosphate buffer and biocompatible as a drug

evaluate anticancer carrier, enhanced the

vitro

release

in CD-MOF

showed

against Human lung permeability of drug and

cancer through MTT significantly improved PAE

assay; in vivo using rats release.

γ-CD- MOF

was

evaluate activities.

In vivo intraocular Improve

pressure (IOP) increase permeability, and

measurement using a enhanced

performed

to

Hydropropyl—

cyclodextrin

(HP-β-CD)

Brinzolamide

(BRZ)

drug

release,

[20]

[21]

introcular

reduction

calibrated

Tono-pen pressure

tonometer

in rats, efficacy.

supported by in vitro

BRZ release in

simulated tear fluid.

Emulsion stability, Stable emulsions under

rheological properties, harsh conditions with high

and gastrointestinal curcumin bioaccessibility;

digestion were all

γ-CD-alg

nanoemultion

(Cyclodextrin)

Curcumin

145

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs

(Guest)

Studies

evaluated in

Findings

Ref.

vitro, promising for bioactive

the delivery.

including

standardized

INFOGEST

digestion

simulate

model

to

human

gastrointestinal

conditions.

The application of CD as a drug delivery agent has

good effectiveness (Figure 3). Cyclodextrins have

shown various beneficial applications in the

pharmaceutical field, including targeted drug

such as alcohol, propylene glycol, and oil. In

addition, cyclodextrin also contributes to

improved product stability and shelf life (Table 2).

These properties give cyclodextrin the potential

to improve drug safety and efficacy [22].

delivery,

drug

encapsulation,

solubility

enhancement, and elimination of toxic solvents

Figure 3. β-CD guest binding mechanism

Crown ether (CEs)-based SDDS

form complexes with various cations. The

presence of empty spaces in CEs molecules can

capture guest molecules [24]. This ability makes

CEs a very useful molecule in various chemical

applications, including in ion separation, catalysis,

and as a component in drug delivery systems.

Oxygen atoms in CEs have an important role as

complexing agents for other molecules [25].

Crown ethers (CEs) are another type of

macrocyclic that have great potential as drug

delivery agents (Figure 4). CEs were synthesized

and published by Pedersen in 1967 [23]. One of

the interesting properties of crown ether is the

presence of electron pairs on the hetero atoms in

its molecular ring, which gives it the ability to

(A) 12-crown-4 (12C4)

(B) 15-crown-5 (15C5)

(C) 18-crown-6 (18C6)

Figure 4. Molecular structure of crown ether [6] (Reprinted with permission)

Table 3. Comparison of crown ethers-based drug delivery

146

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs

(Guest)

Doxorubicin

(DOX)

Studies

Findings

release,

Ref.

Fe₃O_4-SiO_2-meso-SiO₂-

Crown-ethers

In vitro drug release Controlled

was perfomed in buffer ultrasound-triggered

[26]

systems; MTT assay delivery, high loading,

was carried out to and

determine cytotoxicity contrast

against cancer cells. theranostics.

Drug release

strong

MRI

for

Poly(N-

Doxorubicin

(DOX)

was Improve drug release

[27]

[28]

isopropylacrylamide-co-

benzo-18-crown-6-

acrylamide)

characterized using UV- behaviors

Vis in simulated followed

with

enhancing

K⁺

extracellular

intracellular fluids.

and the safety and efficacy

of cancer therapy.

(PNB)

1,2-O-dioleoyl-3-O-{2-[(12-

crown-4)methoxy]ethyl}-

DNA

In

carried

vitro

assay

out

was Could improve DNA

to delivered

by

sn-glycerol

dioleoyl-3-O-{2-[(15-

and

1,2-O-

chacterize

incorporated

drug- liposomes

crown-5)methoxy]ethyl}-

sn-glycerol

(Crown Eter)

2-aminomethyl-18-crown-

6

(Crown Eter)

Clyndamicin

In

vitro

assay

was Improve drug release

[29]

[30]

performed to evaluate of

drug release.

clyndamicin

through liposomes

Aza-crown ethers (Crown Curcumin

Eter)

Preparation

curcumin–nido-

of Enhance

water

soluble of curcumin.

carborane

(SA-CBC

characterization

fluorescence

polymers Morevoer two

and

CBC); curcumin–nido-

by carborane delivery

lifetime systems (SA-CBC and

CBC) were developed

measurement,

transmission electron to

microscopy, and curcumin’s

particle size analysis; in bioavailability,

vitro drug release targeting

studies; and bioactivity

assays evaluating

enhance

stability,

and

tumor cell inhibition.

DDP@18-crown-6 (Crown Cisplatin

Eter)

In vitro for antitumor Improve

solubility,

and

[31]

activity

Cancer

agains

Lung stability

antitumor activity

TiO₂ / 15-crown-5 ether Dopamine

matrix

Evaluation of dopamine Demonstrated

stability when improved

encapsulated in TiO₂ stability

[32]

thermal

and

ether

TiO₂/15-crown-5 sustained

composites; encapsulation

of

characterization using dopamine within the

XRD, SEM, and hybrid matrix,

suggesting potential

thermogravimetric

147

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs

(Guest)

Studies

Findings

Ref.

analysis

protective effects.

to

assess as

a

controlled

release system.

Fluoro-crown

phosphate

(Cyclic-FP-CEs)

ether 5-Fluoroacil

Investigation of fluoro- Exhibited efficient cell

[33]

crown ether phosphate penetration

as cell-permeable potential

carrier; assessment of improving

and

for

a

membrane

permeability

enhancement

hydration

intracellular delivery

of various therapeutic

via molecules by altering

layer hydration barriers.

disruption mechanisms

in vitro

Crown

ether- Fusidic acid Synthesis

and Showed

of antimicrobial activity,

ether- favorable ADMET

fusidic profile, and strong

affinity in

assessment, docking simulations,

ADMET prediction, and supporting further

enhanced

[34]

functionalized fusidic acid derivate

butyl ester

(FABE-CEs)

characterization

crown

functionalized

acid ester; biological binding

activity

molecular

studies

bacterial targets.

docking exploration

against therapeutic

as

a

candidate.

K⁺-responsive

ether-based

copolymer

crown Doxorubicin

amphiphilic (DOX)

Synthesis of

responsive amphiphilic responsive

K⁺- Achieved

ion-

release

for both

[35]

copolymer

incorporating

ether

behavior

crown doxorubicin and gold

moieties; nanoparticles,

evaluation of controlled demonstrating utility

drug and nanoparticle in

release triggered by platforms

smart

delivery

with

potassium ion stimuli.

potential biomedical

applications.

The oxygen atom in the crown ether is in an ideal

position to coordinate with the cation on the

inside of the ring [36]. Complex formation

between crown ethers and cations depends on

the suitability of the size of the crown ether to the

metal ion, the type of solvent used, as well as the

nature of the substituent groups in the crown

ether [37]. The naming of crown ethers is based

on two numbers, where the first number

indicates the total number of atoms in the ring,

while the second number indicates the number

of oxygen atoms [38]. The oxygen atoms in CEs

can be replaced by other atoms that have

coordination ability such as nitrogen [39]. Due to

the special structure possessed by CEs, the

complex formed between CEs and ions is

amphiphilic, where ions form a hydrophilic

center, while the polyether structure forms a

hydrophobic outer part [40]. The amphiphilic

nature of these complexes allows CEs to have

great potential in macrocyclic-based drug

delivery systems (SDDSs) (Table 3). Although CEs

are easy to modify, there are some major

obstacles that hinder their application in the

biomedical field, namely their relatively high

price and the presence of a certain degree of

toxicity [41]. The formation of complexes

between crown ethers and cations is highly

dependent on the relative size of the crown

ethers. compared to the metal ion, the nature of

148

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

the solvent used, and the type of substituent

present in the crown ether (Figure 5). The size of

the crown ether that matches the size of the

metal ion will increase the binding affinity, thus

allowing the formation of a stable complex. In

addition, solvent properties, such as polarity, also

play an important role in facilitating the

interaction between the crown ether and the

cation [42]. Substituents on the crown ether,

either in the form of electron-donating groups or

electron-withdrawing groups, can also affect the

strength and selectivity of binding with certain

metal ions [43].

The development of drug delivery systems based

on CEs is an interesting study in modern

pharmacy. CEs are known to be developed as

delivery systems that are responsive to several

variables [45]. Lee and his co-workers [26]

developed the material Fe₃O₄@SiO₂@meso-

SiO₂@ crown ether (CE) based CEs for

transporting the hydrophobic drug doxorubicin

(DOX). Initially, DOX is deposited in mesoporous

silicon, CEs prevent its release by the interaction

of exogenous cations such as Na⁺ and Cs⁺.

However, when subjected to ultrasound waves or

in an acidic environment (pH 4.0), the interaction

between CEs and cations is disrupted, allowing

controlled release of DOX. Crown ether has also

been reported to be successfully complexed with

bioactive compounds. Echegoyen and co-

workers [46] developed non-ionic liposomes

The ability of CEs to interact with ions makes

them good hosts in ion delivery systems. Bell and

co-workers [40] developed CEs that act as

carriers for certain atoms with therapeutic

effects and produce alpha particles, such as the

based

on

CEs

with

cholesterol-derived

radioisotope

Actinium-225

(²²⁵Ac).

Such

compounds. The addition of cholesterol to the

crown ether aims to ensure that when the

monomer is sonicated in water, stable niosomes

can be formed which are then named

cholestanyl. These studies have uncovered a new

chapter in macrocyclic supramolecule-based

delivery systems such as CEs. CEs also play a

major role in the potential utilization of

supramolecular-based materials in drug delivery

applications.

compounds can be complexed by heterocyclic

CEs with 18 rings and are referred to as macropa.

Research by Monserrat and co-workers [44]

successfully synthesized spherical vesicles from

aza crown ether. The synthesis of the compound

involves the interaction between aza crown ether

which is like a surfactant with silver (I) ions,

producing a complex in aqueous solution.

(A) Compleks of 18C6 with K

(B) 3D model 18C6 binding K⁺

(C) Aza-crown ether

Figure 5. Structure and modeling of 18C6 complex with Potassium [10], aza-crown ether with silver(I)

(Reprinted with permission

SDDS based on Cucurbit[n]urils (CB[n]s)

CB[n]s compound was first synthesized by

Behrend and co-workers (1905) [48], after which

Freeman and co-workers (1981) [49] confirmed

its structure. The characteristic of CB[n]s

structure is its highly symmetrical shape

resembling a flask, with negatively charged

Cucurbit[n]urils (CB[n]s) are a type of macrocyclic

that serve as molecular carriers with various

unique properties. CB[n]s are synthesized

through an acid-catalyzed condensation process

between glycoluryl and formaldehyde. The

149

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

carbonyl cavities at both ends and a hydrophobic

central cavity.

Table 4. Comparison of cucurbit[n]urils-based drug delivery

Types

Drugs (Guest)

Studies

Findings

Ref.

CB[7]

(Cucurbit[7]uril)

Triamterene

In vivo pharmacokinetic Improved

study evaluating the bioavailability, and drug

delivery of triamterene stability; exhibited pH-

encapsulated by CB[7], responsive release

solubility,

[50]

assessing

stability,

solubility, behavior.

and

bioavailability.

CB[8]

(Cucurbit[8]uril)

Doxorubicin

(DOX)

Preparation

supramolecular

nanomedicine

of Enabled self-imaging and

controllable drug release

[51]

from for

cancer

therapy

CB[8]-based amphiphilic applications.

brush copolymer;

evaluation of self-imaging

capability and in vitro

drug release.

CB[7]

(Cucurbit[7]uril)

Nabumetone,

Naproxen

In

calorimetric,

computational studies of inclusion complexes with

host–guest inclusion both drugs.

complexes in aqueous

solution.

vitro

spectroscopic, Enhanced solubility and

[52]

[53]

and formation of stable

CB[6]-polymer

(Cucurbit[6]uril)

Galactose-spmd Synthesis

responsive

of

stimuli- Stimuli-responsive

polymer polymer system enabled

nanocapsules based on controlled

release

of

CB[6]; evaluation of cargo encapsulated cargo.

encapsulation

controlled

triggered

and

release

by

environmental stimuli.

CB[7]-PEG

(Cucurbit[7]uril)

Insulin

In

supramolecular

PEGylation to

insulin properties and behavior of insulin.

stability.

vitro

studies

on Improved

protein

[54]

[55]

stability and modified

modify pharmacokinetic

CB[7]-PEG-

polymer

Oxaliplatin

Development

supramolecular

of Demonstrated

cytotoxicity

low

and

(Cucurbit[7]uril)

polymeric chemotherapy prolonged

formulations; assessment performance, enhancing

anticancer potential.

circulation

150

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs (Guest)

Studies

Findings

Ref.

of

cytotoxicity

and

pharmacokinetics.

CB[7]-Fe₃O₄

FA-ADA

Preparation

of

CB[7]- Improved

therapeutic

[56]

(Cucurbit[7]uril)

functionalized

magnetic efficacy through targeted

nanoparticles; evaluation delivery and imaging-

of imaging-guided cancer guided treatment.

therapy efficacy.

CB[7]-PEG-DSPE Mannose-ADA

(Cucurbit[7]uril)

Construction

of Exhibited

powerful

[57]

supramolecular artificial antibacterial activity and

receptor-modified

macrophages

incorporating

assessment

selective

target sites.

delivery

to

CB[7];

of

antibacterial function and

selective delivery.

CB[7]-HA

(Crown Ether)

Curcumin

Development

hyaluronic

supramolecular

formulations; evaluation curcumin.

of anti-psoriasis activity

and controlled release

properties.

of Enhanced anti-psoriasis

acid-based activity and provided

controlled release

[58]

[59]

of

Cy2-CB[8], Me4- Amiodarone,

CB[8]

(Cucurbit[8]uril)

In vitro inclusion studies Significantly

β- to assess the solubility aqueous

enhancement of poorly multiple

improved

Tamoxifen,

Estradiol,

Albendazole

solubility

of

hydrophobic

via host–guest

soluble drugs in water drugs

using CB[8] derivatives.

complex formation.

CB[n]s are capable of forming host-guest

complexes in 1:1 or 1:2 ratios with various

organic and inorganic guest molecules, where

the guest molecules are encapsulated in their

hydrophobic cavities (Figure 6). The stability of

these complexes is supported by various types of

non-covalent interactions, including hydrogen

bonding, Van der Waals forces, as well as ion-

dipole interactions occurring in the CB[n]s cavity

[29]. Cucurbit[n]urils CB[n]s are a type of

macrocyclic that is quite similar to cyclodextrin

(CD) but has different properties [10]. The

binding of guest molecules to CDs relies on

hydrophobic interactions, where the hydroxyl

groups at the cavity end of CDs face outward and

rarely interact with guest molecules. In contrast,

the binding of guest molecules to CB[n]s depends

on multiple interactions, such as ion-dipole

interactions and hydrophobic interactions [60-

61].

Figure 6. Loading mechanism of cucurbit(7)uril

guest

151

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

In the field of drug delivery, cucurbit[n]uril

(CB[n]s) generally act as delivery media with

controlled release, detoxification agents, and

targeted drug or gene delivery systems. In

addition, CB[n]s can also be assembled into

biomacromolecular structures and have broad

thereby improving the stability of the drug [50].

In addition, CB[7] can also increase the

cholesterol solubility of β-estradiol, potentially

enhancing its pharmacological effectiveness [65].

CB[n]s are also reported to have successfully

enhanced the effectiveness of platinum-based

chemotherapy with cisplatin. Plumb and co-

potential

applications

in

biosensors

and

treatment of various diseases [61]. However, one

of the main obstacles in the development of

CB[n]s is their relatively low solubility and

workers

[66] in

their study successfully

encapsulated cisplatin in CB[7] to increase its

anticancer effectiveness against human ovarian

cancer cells. In vivo studies show that the

CB[7]Cisplatin complex has the potential to be

used in the treatment of drug-resistant cancers

(Table 4).

difficult-to-modify

structure.

CB[n]s

have

hydrophilic surfaces and hydrophobic cavities,

which allow them to form inclusion complexes

with lipophilic drugs to improve their solubility

and stability. CB[5] has a limited cavity size,

making it interact only with small molecules and

is often used as an ion container medium [63].

Meanwhile, CB[7] is the most widely used type

because it has an ideal cavity size, excellent water

solubility, and low toxicity [64]. For example,

CB[7] is known to encapsulate triamterene,

(CB[n]) can also serve as an antidote to prevent

or reduce the toxic side effects of the guest

molecules it encapsulates. For example, CB[7]

was shown to reduce paraquat toxicity by

lowering its concentration in plasma and major

organs in paraquat-poisoned test animals [67].

Figure 7. Illustration of CB-based antidotes [7] in overcoming paraquat (PQ) toxicity [37] (Reprinted with

permission)

In addition, CB[7] also has the potential to be

used as an antidote to neuromuscular blocking

agents. One of the most commonly used

are require this drug [67]. Kuok and co-workers

[68] successfully developed a CB[7]-bedaquiline-

based tuberculosis therapy. Bedaquiline is an

antituberculosis drug that has cardiotoxicity

effects and low water solubility. However,

through the encapsulation process with CB [7],

the solubility of bedaquiline has increased

significantly.

neuromuscular

succinylcholine, but its use often causes serious

side effects. Through the host-guest

blocking

agents

is

encapsulation mechanism, CB[7] can reduce the

toxicity of succinylcholine, thus potentially

improving the safety of therapy for patients who

152

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Data from both in vitro and in vivo tests show

that bedaquiline's cardiotoxicity is reduced, while

edges on the primary and secondary sides

(Figure 8). C[n]As and its derivatives have been

reported to have anticancer, antibacterial and

antiviral activity [70], antituberculosis, and

antifungal [71] activities. As therapeutic drug

carriers, water-soluble C[n]As are synthesized

through sulfonation reactions at the top edge,

incorporation of carboxylic groups at the bottom

edge, or addition of polar functional groups at

the molecular edge [72]. Various small molecules

and biomolecules can be incorporated into the

voids at both edges of C[n]As, including ions,

carbohydrates, proteins, amino acids, peptides,

hormones, and nucleic acids [73-75]. These

inclusion complexes are stabilized by various

interaction forces, such as hydrophobic effects,

ion-dipole interactions, and hydrogen bonding.

its

antimycobacterial

activity

remains

unchanged. This makes the use of CB [7] a

promising strategy to improve the safety and

effectiveness of this drug in tuberculosis therapy.

SDDS based on Calix[n]arenes (C[n]As)

Calix[n]arenes

compounds

(C[n]As)

composed

are

of

macrocyclic

phenol units

connected by methylene bridges (Figure 8), with

a cup-like structure [69]. In general, C[n]As can be

synthesized through the reaction between

phenol and formaldehyde, with the phenolic unit

connected by a methylene group at the meta

position. C[n]As has variable hydrophobic voids

(depending on the phenolic unit) as well as two

Figure 8. Molecular structures of (C[n]As) and (P[n]As)

The unique structure makes C[n]As have a variety

of different isomeric conformations that are

customized based on the phenol unit. Previous

study explained about calix[4]resorcinarenes as

Calix[4]resorcinarenes is a macrocyclic C[4]As

derivative that has 4 resorcinol units connected

with a methylene bridge, creating the molecule to

have 5 different conformations (Figure 9).

a

drug

delivery

application

[76].

(A) Chair

(B) Boat

(C) Diamond

(D)

Figure 9. Conformation of calix [4] resorsinaren isomers: (A) Seat; (B) Boat; (C) Diamond; (D) Crown; (E)

Saddle [10,76]. (Reprinted wtih permission).

153

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Table 5. Comparison of calix[n]arenes-based drug delivery

Types

PTX-CPT-P4C6

(Calixarene)

Drugs (Guest)

Carboplatin,

Paclitaxel

Studies

Findings

and Demonstrated

Ref.

[77]

Development

physicochemical

efficient

molecular

enhanced

responsive complexation- drug activity against

characterization of a pH- loading,

based delivery system; tumor

assessment of molecular excellent

cells,

and

loading

biocompatibility,

efficiency, biocompatibility

and vitro.

in

anticancer efficacy.

Calix[8]arenes

(Calixarene)

Glycosylation

conjugates

Synthesis and biological Effectively prevented

[78]

evaluation

of tumor cell migration

self- and proliferation,

vaccine supporting potential

multicomponent

adjuvant

candidates tethered on a applications

calixarene platform; cancer

studies of tumor cell immunotherapy.

migration and

proliferation inhibition.

Formulation of

in

P-Sulfocalix[6]arene

(Calixarene)

Doxorubicin

(DOX)

P- Provided low toxicity,

[79]

[80]

sulfocalix[6]arene

nanocarriers

controlled

for behavior,

release

and

Doxorubicin delivery; in sustained anticancer

vitro evaluation of release efficacy.

kinetics and cytotoxicity

against cancer cells.

Calix[6]arene

carboxylic

hexa- Paclitaxel (PTX) Preparation

and Achieved

of sustained

slow,

release

drug

acid

characterization

amphiphilic

nanoparticles as carriers loading

(Calixarene)

calixarene and

high

capacity,

for Paclitaxel; in vitro improving delivery of

release and loading hydrophobic agents.

capacity assessment.

P-Phosphonated-

calix[4]arene

(Calixarene)

Paclitaxel (PTX) Design and evaluation of Enabled

pH-

drug

and

[81]

[82]

pH-responsive

responsive

phosphonated calixarene release

nanovesicles for Paclitaxel enhanced anticancer

delivery; analysis of drug activity.

activity enhancement.

βCD-CA4

giant Docetaxel

Fabrication of Docetaxel- Demonstrated slow

amphiphiles

(Calixarene)

loaded

from

cyclodextrin/calixarene

nanoparticles drug

release

and

β- improved

aqueous

solubility,

giant surfactants; studies contributing

to

of solubility, release, and higher cytotoxicity in

cytotoxic effects in cancer prostate cancer and

cells.

glioblastoma cells.

154

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Types

Drugs (Guest)

Studies

Findings

Ref.

Tetra-para-

phosphonomethyl

calix[4]arene

Carboplatin

Investigation of shear- Improved

drug

efficiency

controlled

enhancing

[83]

induced

complexation

carboplatin loading

within and

phospholipid-mimicking

release,

calixarene

evaluation

efficiency

profile.

cavities; anticancer efficacy.

loading

release

of

and

P-Sulfonatocalix[4]

arene (Calixarene)

Temozolomide Encapsulation

Temozolomide

of Significantly

in increased

[84]

calixarene nanocapsules; therapeutic efficacy

assessment of stability, and

encapsulation efficiency, stability

improved

and

therapeutic

against glioblastoma.

Chaperone for Development

in

vitro/in

efficacy efficiency

Temozolomide.

vivo encapsulation

of

P-Sulfonatocalix[4]

arene

of Enhanced anticancer

p- activity and enabled

[85]

[86]

anticancer

drugs

amphiphilic

sulfonatocalix[4]arene as controlled release of

a supramolecular “drug hydrophobic drugs.

chaperone”; evaluation of

anticancer drug delivery

and release kinetics.

Mannosylated-

calix[4]arene

Doxorubicin

(DOX)

Dynamic self-assembly of Demonstrated

mannosylated calixarene responsive release

pH-

micelles; characterization and

of pH-responsive release improved

significantly

delivery

behavior

and

drug and

for hydrophobic drugs.

anticancer

solubility

of

encapsulation

hydrophobic

agents.

This configuration allows for a complex array of

'host-guest' interactions, where guest molecules

can bind to the host through various non-

infectious diseases, as well as gene-based

therapies.

C[n]As can also be integrated as micelle- and

nanoparticle-based delivery. In their research, Li

and co-workers [77] synthesized phosphorylated

C[4]As that can encapsulate camptothecin and

paclitaxel in the form of nanovesicles as an

application of tumor inhibition by increasing

therapeutic effectiveness. Research by Drakalska

and co-workers [87] also synthesized PEGylated

tert-butyl C[4]A which was applied as a micelle-

based drug carrier and was able to increase the

solubility of curcumin. With various types of

modifications that exist for C[n]A illustrates that

the supramolecular macrocyclic C[n]A-based

delivery has enormous potential in the world of

covalent

bonding

mechanisms,

such

as

hydrophobic interactions, Van der Waals forces,

and hydrogen bonding. These properties make

this

material

an

efficient

drug

delivery

biomaterial candidate, capable of improving the

stability and bioavailability of active compounds

in the body. In addition, similar characteristics

are also found in the C[n]As units, which are

known

to

have

four

different

possible

conformations, allowing high structural flexibility

in conforming to different types of guest

molecules. This flexibility expands their potential

applications in more specific and targeted drug

delivery systems, including in cancer therapy,

155

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

modern drug delivery systems (Figure 10).

Bandela and co-workers [88] synthesized

cholesterol-modified C[4]arene to improve the

delivery and storage efficiency of drugs such as

doxorubicin, curcumin, tocopherol. The results

showed that molecular loading with cholesterol-

ethers connected at the para position of the

benzene ring via a methylene bridge [90]. P[n]As

was first introduced by Ogoshi and co-workers

(2008) [91]. Compared to the cup-like structure of

C[n]As connected via a meta-bridge, P[n]As is

composed

connecting 1,4-dialoxybenzene units at the para

position (Figure 11), forming unique

of

methylene

bridges

(-CH₂-)

modified

C[4]arene

can

provide

good

reversibility for 4 cycles of use. This is because

the transition of C[4]arene synthesis from sol to

gel showed high efficiency. C[n]As is also

reported to be applicable in gene delivery

therapy. Solubility and toxicity are often

obstacles in the development of C[n]A-based

drug delivery. Modifications are often made to

overcome this problem (Table 5). For example,

a

architecture. which is rigid with a pillar-like

shape. Due to its symmetrical structure, P[n]As

has been utilized to create various complex

supramolecular systems [92].

P[n]As has the ability to improve the stability,

solubility, as well as bioavailability of the guest

molecules it encapsulates. However, the water

solubility of ordinary P[n]As is still limited. The

structure on both sides of P[n]As can be well

modified, and most of its functionalized

derivatives exhibit good water solubility, low

toxicity, and selective inetraction to guest

molecules [93]. Among these derivatives,

carboxyl-modified P[n]As with water-soluble

ability (WP[n]As) is widely used in drug delivery

applications (Table 6). Shangguan and co-

workers [94] performed carboxyl modification on

P[6]As (WP[6]As) as an encapsulant for the

anticancer drug tamoxifen to improve the

bioactivity and solubility of the drug. Research by

Wheate and co-workers [95] compared the

potential of carboxylated P[n]As with water-

soluble (WP[6]As/WP[7]As) in drug delivery and

biodiagnostic applications. Both types of WP[n]As

are capable of forming host-guest complexes

with various drug molecules such as memantine,

chlorhexidine hydrochloride, and proflavin.

These interactions are stabilized by hydrophobic

effects within the molecular cavity, as well as

hydrogen bonding and electrostatic interactions

at the portals. In addition, WP[n]As shows low

toxicity to cells, except in high doses or after

prolonged continuous exposure

the

development

of

hypoxia-responsive

molecular containers based on carboxylated

azocalix[4]arene was carried out in tumor

therapy applications [89].

Figure 10. Schematic illustration of hypoxia-

responsive drug delivery based on

CAC[4]A Modified from Zhang [50]

CAC[4]A showed good ability in the recognition of

“host-guest” complexes for 12 chemotherapeutic

drugs, showing good versatility in cancer therapy.

SDDS-based Pillar[n]arenes

Pillar[n]arenes (P[n]As) are cyclic oligomers

consisting of hydroquinone or hydroquinone

156

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Figure 11. Structure and 3d illustration of P[n]As

Table 6. Comparison of pillar[n]arene-based drug delivery

Type

Drug

(Guest)

Studies

Findings

Ref.

deca-

Amikacin

In vitro assay using Enabled

HepG2

water-

cells; soluble delivery and

of targeted cellular

[97]

carboxylatopillar[5]arene)

(pillar[n]arene)

evaluation

endocytosis-

mediated

uptake of amikacin,

uptake improving potential

and water solubility for

intracellular

with fluorescence antibiotic therapy.

labeling (CF@4).

WP6

(Pillar[6]arene)

Tamoxifen

Investigation

water-soluble

complexation

of Improved

solubility

drug

and

[94]

[98]

enhanced bioactivity

vitro of tamoxifen in

release assays and aqueous

UV spectroscopic environments.

analysis.

In vitro release Provided controlled

using

in

pillar[6]arene

Doxorubicin

(DOX)

behavior assessed drug

under physiological demonstrated

pH

release

and

anti-

conditions; multidrug resistance

evaluation

multidrug

resistance

of properties, enhancing

chemotherapeutic

(MDR) potential.

reversal effects.

pillar[5]arene-[2]rotaxane

Doxorubicin

(DOX), Prodrug

Responsive

behavior assessed responsive

under in vitro pH and

Achieved

pH-

release

specific

[99]

conditions;

evaluation

mitochondrial

targeting

mitochondrial

of imaging capability for

targeted

cancer

using therapy.

fluorescence

imaging

techniques.

Trp-pillar[5]arene-galactose

Doxorubicin

(DOX)

In vitro MTT assay Enabled

for cytotoxicity; delivery

synergistic

[100]

with

of cytotoxicity

low

and

evaluation

release

and

kinetics enhanced targeting of

targeting cancer cells.

toward

efficiency

cancer cells.

157

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Type

Drug

(Guest)

Studies

Findings

Ref.

SeSe-[P5]₂-Man-NH₃

Doxorubicin

(DOX)

n vitro MTT assay Demonstrated TME-

evaluating tumor responsive behavior

[101]

microenvironment

(TME)-responsive

and effective targeted

delivery for cancer

release

and chemotherapy.

targeted delivery.

N-methylimidazolium-

pillar[5]arene

Doxorubicin

(DOX)

In vitro release Exhibited

low

and

slow-

[102]

assay

spectroscopy;

cytotoxicity

by

UV cytotoxicity

sustained,

release

behavior,

evaluation via MTT supporting

assay.

applications

controlled

system.

as

release

a

T-SRNs-carboxylate-

pillar[5]arenes

Doxorubicin

(DOX)

In vitro evaluation Showed

of pH-responsive responsive,

behavior and prolonged

pH-

[103]

[104]

release

sustained release profile suitable for

under

acidic tumor-targeted drug

conditions.

delivery.

Acetal-pillar[5]arene

Paclitaxel

Cargo

Increased bioactivity

encapsulation

confirmed

confocal

and

provided

by targeted delivery to

laser cancer cells with pH-

responsive release.

scanning

microscopy (CLSM);

in vitro assays for

biological

assessment.

In

activity

2,2′-biphen[4]arene

Palmatine,

berberine

vitro Induced

fluorescence

strong

[105]

fluorescence

titration

binding

studies; enhancement

complex demonstrated

and

high

characterization

binding affinity to

using

spectroscopy.

NMR alkaloid guest

molecules,

supporting

applications

detection

in

and

delivery systems.

CP[5]A can be well used as a pH-responsive

based delivery, or competitive interaction

between cargo molecules that will create

sustained release in drugs such as rhodamine B

(RhB), calcein, and doxorubicin hydrochloride

(DOX). In addition, P[n]As is also known to have

the ability to detoxify by encapsulating toxins,

making this delivery system has great potential in

its utilization in the modern pharmaceutical field

[58]. Various studies have certainly been

macrocyclics as supramolecular-based drug

delivery.

Conclusion

The various studies that have been discussed

prove

that

macrocyclic

compounds

have

enormous potential in their utilization as modern

drug delivery systems with various unique

properties according to their application.

Cyclodextrins

(CDs),

crown

ethers

(CE),

conducted

to

identify

several

uses

of

cucurbit[n]urils (CB[n]s), calix[n]arenes (C[n]As)

158

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

and pillar[n]arene (P[n]A) are some of the many

future. Chemical Society Reviews. 2017;46.

https://doi.org/10.1039/C6CS00898D

types

of

macrocyclic

supramolecular

modifications that have unique capabilities as

drug delivery systems. Properties such as stable

[4].

[5].

[6].

Wu, J. R., Wu, G & Yang. Y. W. Pillararene-

Inspired Macrocycles: From extended

Pillar[ n]arenes to Geminiarenes. Accounts

host-guest

interaction,

stability,

solubility,

surface area and biocompatibility make these

compounds play an important role in the

modification of drug delivery systems in the

modern pharmaceutical world.

of

Chemical

Research,

2022;55(21).

https://doi.org/10.1021/acs.accounts.2c00

555.

Wu, D., Wang, J., Du, X., Cao, Y., Ping, K &

Liu,

supramolecular theranostics. Joirnal of

Nanobiotechnology, 2024;9(22),235).

D.

Cucurbit[8]uril-based

Acknowledgement

The authors would like to thank to NPBC Lab for

research support and technical resources used in

preparing this review. We also appreciate the

constructive feedback from our colleagues at

Universitas Jambi and Taipei Medical University,

which helped improve the clarity and quality of

the manuscript.

https://doi.org/10.1186/s12951-024-

02349-z

Yang, Y., Li, P., Feng, H., Zeng, R., Li, S &

Zhang,

Q.

Macrocycle-Based

Supramolecular Drug Delivery Systems: A

Concise Review. Molecules, 2024;29, 3828.

https://doi.org/10.3390/molecules291638

28

Webber, M, J., & Langer, R. Drug delivery by

supramolecular design. Chemical Society

Author Contributions

[7].

[8].

Conceptualization, M. F. N. S and I. L. T.;

Methodology, M. F. N. S.; Validation, I. L. T and Y.

N.; Investigation, M. F. N. S.; Resources, I. L. T.;

Writing – Original Draft Preparation, M. F. N. S.;

Writing – Review & Editing, I. L. T and Y. N.;

Visualization, M. F. N. S.; Supervision, I. L. T.;

Project Administration, I. L. T. and M. F. N. S.

Review,

2017;46,

6600.

https://doi.org/10.1039/C7CS00391A

Geng, W. C., Jiang, Z. T., Chen, S. L & Guo, D.

S. Supramolecular interaction in the action

of

Sciences,

https://doi.org/10.1039/D3SC04585D

drug delivery systems. Chemical

2024;15, 7811.

[9].

Poulson, B.G.; Alsulami, Q.A.; Sharfalddin,

A.; El Agammy, E.F.; Mouffouk, F.; Emwas,

Conflict of Interest

A.-H.;

Jaremko,

L.;

Jaremko,

M.

The authors declare no conflict of interest.

References

Cyclodextrins: Structural, Chemical, and

Physical Properties, and Applications.

Polysaccharides.

https://doi.org/10.3390/polysaccharides30

10001

[1].

Deng, J. H., J. Luo, Y.-L. Mao, S. Lai, Y.-N.

Gong, D.-C. Zhong, T.-B. Lu, π-π stacking

interactions: Non-negligible forces for

2022;

3,

1-31.

stabilizing

porous

supramolecular

[10]. Neaz,

S.,

Alam,

M.M.,

Imran,

A.B.

frameworks. Science Advances. 2020;6(2),

eaax9976.

Advancements

controlled drug delivery: Insights into

pharmacokinetic and pharmacodynamic

in

cyclodextrin-based

https://doi.org/10.1126/sciadv.aax9976

Tong, F., Zhou, Y., Xu, Y., Chen, Y.,

Yudintceva, N., Shevtsov, M & Gao, H.

Supramolecular nanomedicines based on

host-guest interactions of cyclodextrins.

Exploration (Beijing). 2023;3(4)20210111.

https://doi.org/10.1002/EXP.20210111

Zhou, J., Yu, G & Huang, F. Supramolecular

[2].

[3].

profiles.

Heliyon,

2024;

10(e39917).

https://doi.org/10.1016/j.heliyon.2024.e39

917\

[11]. Vinodh, M.; Alipour, F.H.; Mohamod, A.A.;

Al-Azemi, T.F. Molecular Assemblies of

Porphyrins and Macrocyclic Receptors:

Recent Developments in Their Synthesis

and Applications. Molecules, 2012; 17,

11763-11799.

chemotherapy

based

on

host–guest

molecular recognition: a novel strategy in

the battle against cancer with a bright

159

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

https://doi.org/10.3390/molecules171011

763

[12]. Akkari, A. C. S., E. V. R. Campos, A. F.

Keppler, L. F. Fraceto, E. D. Paula, G. R.

Tófoli & D. R. D. Araujo. Budesonide-

Technology,

2018; 37: 21712185. https://doi.org/10.100

2/adv.21876.

[18]. Rizvi S.S.B, Akhtar, N., Minhas, M.U.,

Mahmood A, Khan KU. Synthesis and

hydroxypropyl-β-cyclodextrin

inclusion

Characterization

of

Carboxymethyl

complex inbinary poloxamer 407/403

system for ulcerative colitis treatment:

Aphysico-chemical study from micelles to

Chitosan Nanosponges with Cyclodextrin

Blends for Drug Solubility Improvement.

Gels,

2022

;8(1):55.

hydrogels.

Biointerfaces

https://doi.org/10.1016/j.colsurfb.2015.11.

048

Colloids

and

2016;

Surfaces

B:

https://doi.org/10.3390/gels8010055

[19]. Li, H., Jie, Z., Caifen, W., Wei Q., Xiaoxiao, H.,

Jiabin, T., Lin, Y., Guoqing, Z., Xiaohong, R,

Zegeng, L & Jiwen, Z. Paeonol loaded

138,

138–147.

[13]. Venuti, V., Cannavà, C., Cristiano, M. C.,

Fresta, M., Majolino, D., Paolino, D.,

Stancanelli, R., Tommasini, S & Ventura, C.

cyclodextrin

particles for treatment of acute lung injury

via inhalation. International Journal of

Pharmaceutics,

metal-organic

framework

A.

A

characterization

study

of

2020;587,

119649.

resveratrol/sulfobutylether-β-cyclodextrin

inclusion complex andin vitro anticancer

https://doi.org/10.1016/j.ijpharm.2020.119

649.

activity.

Biointerfaces,

https://doi.org/10.1016/j.colsurfb.2013.11.

025

Colloids

and

Surfaces

115. 22–28.

B:

[20]. Wang, F., Bao, X., Fang, A., Li, H., Zhou, Y.,

Liu, Y., Jiang, C., Wu, J & Song, X. 2018.

Nanoliposome-Encapsulated

2014;

Brinzolamide-hydropropyl-β-cyclodextrin

Inclusion Complex: A Potential Therapeutic

Ocular Drug-Delivery System. Frontiers in

[14]. Ha, W., Yu, J., Song, X. Y., Chen, J & Shi, Y. P.

Tunable

temperature-responsive

supramolecular hydrogels formed by

prodrugs as a codelivery system. ACS

Applied Material Interfaces, 2014. 6(13).

10623–10630.

https://pubs.acs.org/doi/10.1021/am5022

864

Pharmacology,

2018;

9.

https://doi.org/10.3389/fphar.2018.00091

[21]. Wang, C., Xiaojing, L., Shangyuan, S., David,

J., McClements, Long, C., Jie, L., Aiquan, J.,

Jinpeng, W., Zhengyu,

Preparation, characterization and in vitro

J

&

Chao, Q.

[15]. Yakupova, L.R.; Skuredina, A.A.; Markov,

P.O.; Le-Deygen, I.M.; Kudryashova, E.V.

Cyclodextrin Polymers as a Promising Drug

Carriers for Stabilization of Meropenem

Solutions. Applied Science. 2023; 13, 3608.

https://doi.org/10.3390/app13063608

[16]. Bai H, Wang J, Phan CU, Chen Q, Hu X, Shao

G, Zhou J, Lai L, Tang G. Cyclodextrin-based

digestive

synergistically

cyclodextrin/sodium

Food Research International, 2022;160.

111634.

https://doi.org/10.1016/j.foodres.2022.111

634

behaviors

of

emulsions

by γ-

stabilized

caseinate/alginate.

[22]. Welliver, M., & McDonough, J. P. Anesthetic

Related Advances with Cyclodextrins. The

Scientific World Journal, 2007;7,364–371.

https://doi.org/10.1100/tsw.2007.83

[23]. Pedersen, C.J. Cyclic polyethers and their

complexes with metal salts. Journal of the

American Society of Chemistry, 1967; 89.

7017–7036.

host-guest

regorafenib

treatment.

complexes

loaded

with

cancer

for

colorectal

Nature

Communication,

2021;3;12(1):759.

https://doi.org/10.1038/s41467-021-

21071-0.

[17]. Khalid Q, Ahmad M, UsmanddMinhas M.

Hydroxypropyl-β-cyclodextrin

hybrid

https://doi.org/10.1021/ja01002a035

[24]. Grobelny, Z., Stolarzewicz, A., Morejko-Buz,

B., Bartsch, R. A., Yamato, K., Fernandez, F.

nanogels as nano-drug delivery carriers to

enhance the solubility of dexibuprofen:

Characterization, in vitro release, and

acute oral toxicity studies. Advance Polymer

A

&

Maercker, A. Preparation and

Decomposition of Potassium

160

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Alkalide−Lipophilic

Crown

Ether

https://doi.org/10.1016/j.dyepig.2024.112

428

[31]. Gao, Y.; Huang, Y.; Ren, C.; Xiong, S.; Guo,

X.; Zhao, Z.; Guo, L.; Huang, Z. Construction

Complexes in Tetrahydrofuran. Journal of

Organic Chemistry, 2002;67(22). 7807–7812.

https://dx.doi.org/10.1021/jo026086r

[25]. Qian, Y., Wu, Y., Qiu, S., He, X., Liu, Y., Kong,

X. Y., Tian, W., Jiang, L & Wen, L. A.

Bioinspired Free-Standing 2D Crown-Ether-

Based Polyimine Membrane for Selective

Proton Transport. Angewandte Chemie

of

Cisplatin-18-Crown-6

Complexes

Through Supramolecular Chemistry to

Improve Solubility, Stability, and Antitumor

Activity. International Journal of Molecular

Sciences,

2024;25,

13411.

International

e202300167.

https://doi.org/10.1002/anie.202300167

[26]. Lee, S. F., Zhu, X. M., Wang, Y. X. Xuan, S. H.,

You, Q., Chan, W. H., Wong, C. H., Wang, F.,

Yu, J. C & Cheng, C. H. Ultrasound, pH, and

Edition,

2023;16(8)

62.

https://doi.org/10.3390/ijms252413411.

[32]. Aragón, P. V., Mónica, R. J. F., Angélica, V. G

& Miriam, E. F. Study of the stability of

dopamine encapsulated in TiO₂and

TiO2/15-crown-5 ether matrix. Ceramics

International, 2024; 50(7). 10959-10966.

https://doi.org/10.1016/j.ceramint.2023.12

.412.

magnetically

coated core/shell nanoparticles as drug

responsive

crown-ether-

encapsulation and release systems. ACS

Applied Materials

&

Interfaces Journal,

2013;5(5).

1566–1574.

Phosphate as Efficient Cell-Permeable

Drug Carrier by Disrupting Hydration

Layer. Journal of the American Chemical

https://doi.org/10.1021/am4004705

[27]. You, X., Xiao-Jie, J., Fan, H., Yuan, W.,

Zhuang, L., Wei, W., Rui, X & Liang-Yin, C.

Polymersomes with Rapid K+-Triggered

Drug Release Behaviors. ACS Applied

Society,

2024;146 (33),

23406-23411.

https://doi.org/10.1021/jacs.4c06464

[34]. Sultan, H., Arshad, N & Lateef, M. Novel

Crown Ether-Functionalized Fusidic Acid

Materials

&

Interfaces,

2017;

9(22).

https://doi.org/10.1021/acsami.7b05701

[28]. Angelini, G., Michela, P., Giovanna, M.,

Milvia, M & Carla, G. Neutral liposomes

containing crown ether-lipids as potential

DNA vectors. Biochimica et Biophysica Acta

Butyl

Ester:

Synthesis,

Biological

Evaluation, In Silico ADMET, and Molecular

Docking

2033.

Studies. Molecules, 2025;30(9),

https://doi.org/10.3390/molecules300920

(BBA)

2506-2512.

https://doi.org/10.1016/j.bbamem.2013.06

.003

–

Biomembranes, 2013;1828(11).

33

[35]. Wang, X., Zheng, X., Liu, X., Zeng, B., Xu, Y.,

Yuan, C & Dai, L. K⁺-Responsive Crown

Ether-Based

Amphiphilic

Copolymer:

[29]. Tasharrofi, N., Nourozi, M. & Ahmadifard,

Z. Development and Optimization of a

Novel Crown Ether-Incorporated Liposome

for Improved Ocular Drug Delivery.

Synthesis and Application in the Release of

Drugs and Au Nanoparticles. Polymers,

2022;

14

(3),

406.

https://doi.org/10.3390/polym14030406

[36]. Bonnin, M.A., and Feldmann, C. Insights of

the Structure and Luminescence of

BioNanoSciences,

2025;

15,261

https://doi.org/10.1007/s12668-025-

01867-w

Mn2+/Sn2+-Containing

Crown-Ether

[30]. Chai, T., Mengtong, Z., Shuo, W., Jiankang,

F., Xibin, F., Shihe, S., Chichong, L & Guofan,

J. Curcumin/nido-carborane complexes

incorporated with crown ether/sodium

Coordination Compounds.

Inorganic

Chemistry, 2021;60(19), 14645–14654

https://doi.org/10.1021/acs.inorgchem.1c0

1662

alginate

encapsulated

drug

delivery

[37]. Gokel, G. W., Barbour, L. J., Wall, S. L. D &

Meadows, E. S. Macrocyclic polyethers as

probes to assess and understand alkali

metal cation-π-interactions. Coordination

Chemistry Reviews, 2001; 222(1),127–154.

strategies exhibit pH-responsive release

and enhanced in vitro anti-tumor activity.

Dyes and

Pigments, 2024;231,112428.

161

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

http://dx.doi.org/10.1016/S0010-

8545(01)00380-0

Synthesis to Applications. Applied Sciences,

2022;

12,

1102.

[38]. Gokel, G.W. Crown Ethers and Cryptands.

Monograph in Supramolecular Chemistry;

The Royal Society of Chemistry: London,

https://doi.org/10.3390/app12031102

[46]. Echegoyen, L. E., Hernandez, J.C., Kaifer,

A.E., Gokel, G.

W

&

Echegoyen, L.

England,

1991.

Aggregation of Steroidal Lariat Ethers: The

First Example of Nonionic Liposomes

(Niosomes) Formed from Neutral Crown

Ether Compounds. Journal of the Chemical

Society, Chemical Communication, 1988;

836–837.

https://doi.org/10.1039/9781788010917

[39]. Bell, M. M., Gutsche, N.T., King, A.P.,

Baidoo, K.E., Kelada, O.J., Choyke, P.L &

Escorcia, F.E. Glypican-3-Targeted Alpha

Particle

Carcinoma.

Therapy

for

Hepatocellular

2020;26(4).

Molecules,

https://doi.org/10.1039/c39880000836

[47]. Muheyati, M., Wu, G., Li, Y., Pan, Z., & Chen,

https://doi.org/10.3390/molecules260100

04

Y.

based

nanobiotechnology, 2024;

Supramolecular

on cucurbiturils. Journal

22(1),

nanotherapeutics

[40]. Chen, L., Zhang, H. Y. & Liu, Y. High affinity

of

790.

crown

ether

complexes

in

water:

Thermodynamic analysis, evidence of

crystallography and binding of NAD+.

Journal of Organic Chemistry, 2012. 77.

9766–9773.

https://doi.org/10.1186/s12951-024-

03024-z

[48]. Behrend, R., E. Meyer & F. Rusche. Ueber

Condensationsproducte RUS Glycoluril und

formaldehyd. Justus Liebigs Annalen der

https://doi.org/10.1021/jo301911w

[41]. You, X. R., Ju, X. J., He, F., Wang, Y., Liu, Z.,

Wang, W., Xie, R & Chu, L. Y. Polymersomes

with Rapid K+-Triggered Drug Release

Behaviors. ACS Applied Material Interfaces.

Chemie,

1905;

339,

1.

http://dx.doi.org/10.1002/jlac.1905339010

2

[49]. Freeman, W. A., Mock, W. L & Shih, N. Y.

2017;

9,

22,

19258–19268.

Cucurbituril.

Journal

of

the Americal

https://doi.org/10.1021/acsami.7b05701

[42]. Chehardoli. G., & A. Bahmani. The role of

Chemical Society, 1981;103. 24. 7367–7368.

https://doi.org/10.1021/ja00414a070

crown

ethers

in

drug

delivery.

[50]. Ma, W. J., Chen, J. M., Jiang, L., Yao, J & Lu, T.

B. The delivery of triamterene by cucurbit

Supramolecular Chemistry, 2019; 31(4), 221-

238,

https://doi.org/10.1080/10610278.2019.15

68432

[7]uril:

pharmacokinetics

Pharmaceutics,

Synthesis,

structures

and

study.

10,

Molecular

4698–4705.

2013;

[43]. Oral, I., Ott, F., Abetz, V. Thermodynamic

study of crown ether–lithium/magnesium

complexes based on benz-1,4-dioxane and

https://doi.org/10.1021/mp400529m

[51]. Wu, D., Li, Y., Yang, J., Shen, J., Zhou, J., Hu,

Q., Yu, G., Tang,

Supramolecular

G

&

Chen, X.

its

homologues.

Physical

Chemistry

Nanomedicine

Chemical Physics, 2022; 24, 11687-11695,

https://doi.org/10.1039/D2CP01076C

Constructed from Curcurbit[8]uril-Based

Amphiphilic Brush Copolymer for Cancer

[44]. Monserrat, K., Gratzel, M & Tundo, P. Light-

Induced Charge Injection in Functional

Crown Ether Vesicles. Journal of the

American Chemical Society, 1980; 102(17).

5521–5529.

Therapy.

ACS

Applied

Material

Interfaces. (2017). 9. 51. 44392–44401.

https://doi.org/10.1021/acsami.7b16734

[52]. Klarić, D.; Borko, V.; Parlov Vuković, J.;

Pilepić, V.; Budimir, A.; Galić, N. Host–Guest

https://doi.org/10.1021/ja00537a018

Interactions

Nabumetone

Spectroscopic, Calorimetric, and

Studies

Solution. Molecules. 2025, 30,

https://doi.org/10.3390/molecules301225

58

of

Cucurbit[7]uril

and Naproxen:

DFT

with

[45]. Ullah, F.; Khan, T.A.; Iltaf, J.; Anwar, S.; Khan,

M.F.A.; Khan, M.R.; Ullah, S.; Fayyaz ur

Rehman, M.; Mustaqeem, M.; Kotwica-

Mojzych, K.; et al. Heterocyclic Crown

Ethers with Potential Biological and

in

Aqueous

2558.

Pharmacological

Properties:

From

162

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

[53]. Kim, E., D. Kim, H. Jung, J. Lee, S. Paul, N.

Selvapalam, Y. Yang, N. Lim, C. G. Park & K.

Kim. 2010. Facile, Template-Free Synthesis

[60]. Das, D., Assaf, K.I., Nau, W.M. Applications

of Cucurbiturils in Medicinal Chemistry and

Chemical Biology. Frontiers in Chemistry.

2019;7.

of

Stimuli-Responsive

Polymer

Nanocapsules for Targeted Drug Delivery.

Angewandte Chemie International Edition.

https://doi.org/10.3389/fchem.2019.00619

[61]. Kim, K., Selvapalam, N & Oh, D. H.

Cucurbiturils—A New Family of Host

Molecules. Journal of Inclusion Phenomena

and macrocyclic chemistry, 2004; 50, 31–36.

http://dx.doi.org/10.1007/s10847-004-

8835-7

14:

49(26):

4405-8.

https://doi.org/10.1002/anie.201000818

[54]. Webber, M. J., E.A. Appel, B. Vinciguerra,

A.B. Cortinas, L.S. Thapa, S. Jhunjhunwala,

L. Isaacs, R. Langer, & D.G. Anderson. 2016.

Supramolecular

PEGylation

of

biopharmaceuticals, Proceedings of the

National Academy of Sciences of the United

States of America. 113 (50) 14189-14194,

https://doi.org/10.1073/pnas.1616639113.

[55]. Chen, H., Yueyue, C., Han, W., Jiang-Fei, X.,

Zhiwei, S & Xi, Z. Supramolecular polymeric

chemotherapy based on cucurbit[7]uril-

PEG copolymer. Biomaterials, 2018; 178

697-705.

https://doi.org/10.1016/j.biomaterials.201

8.02.051 .

[56]. Yue, L., C. Sun, T. H. C. H. T. Kwong & R.

Wang. 2020. Cucurbit[7]uril-functionalized

magnetic nanoparticles for imaging-guided

https://doi.org/10.1016/j.molstruc.2009.04

.022

[64]. Zhang, X., Xu, X., Li, S., Wang, L. H., Zhang, J

& Wang, R. A systematic evaluation of the

biocompatibility of cucurbit[7]uril in mice.

cancer

Chemistry

therapy.

Journal

2020,

of

8,

Material

Scientific

Reports,

2018;

8.

8819.

B,

2749.

https://doi.org/10.1038/s41598-018-

27206-6

https://doi.org/10.1039/D0TB00306A

[57]. Cheng, Q., M. Xu, C. Sun, K. Yang, Z. Yang, J.

Li, J. Zheng, Y. Zheng & R. Wang. 2022.

[65]. Lazar, A. I., Biedermann, F., Mustafina K. R.,

Assaf, K. I., Hennig, A & Nau, W. M.

Enhanced antibacterial function of

supramolecular artificial receptor-

modified macrophage (SAR-Macrophage).

Material Horizon, 2022, 9, 934.

https://doi.org/10.1039/D1MH01813B

a

Nanomolar

Cucurbit[n]urils:

Applications. Journal of the American

Chemical Society, 2016; 138 (39), 13022–

13029.

Binding

of

Steroids

to

and

Selectivity

[58]. Ding, Y., Jianwen, W., Xingping, Q., Wenting,

G., Long, X., Ying, Z., Yonghua, Z., Jingwei, L.,

Shengke, L., Greta, S. P. M & Ruibing, W.

https://doi.org/10.1021/jacs.6b07655

[66]. Plumb, J. A., B. Venugopal, R. Oun, N.

Gomez-Roman,

Venkataramanan

Cucurbit[7]uril

Y.

Kawazoe,

N. J.

encapsulated

cisplatin

pharmacokinetic effect. Metallomics, 2012;

(6), 561.

https://doi.org/10.1039/c2mt20054f

N.

Wheate.

cisplatin

S.

Hyaluronic

acid-based

supramolecular

&

medicine with polyamines sequestration

capability for cooperative anti-psoriasis.

Carbohydrate Polymers, 2022; 296. 119968.

https://doi.org/10.1016/j.carbpol.2022.119

968.

overcomes

resistance via a

4

[59]. Vinciguerra, B., P. Y. Zavalij & L. Isaacs.

[67]. Zhang, X., Xu, X., Li, S., Li, L., Zhang, J &

2015.

Properties of Cucurbit[8]uril Derivatives.

ACS Organic Letters, 2015; 17(20).

Synthesis

and

Recognition

Wang, R. A Synthetic Receptor as a Specific

Antidote

Theranostics,

for

Paraquat

2019; 9.

Poisoning.

633–645.

https://doi.org/10.1021/acs.orglett.5b0255

8

https://doi.org/10.7150/thno.31485

163

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

[68]. Kuok, K. I., In Ng, P. C., Ji. X., Wang. C., Yew.

W. W., Chan. D. P. C., Zheng, J., Lee, S. M. Y

& Wang, R. Supramolecular strateg for

reducing the cardiotoxicity of bedaquiline

[76]. Curtis, A. D. M, & Hoskins, C. Simple

Calix[n]arenes and Calix [4]resorcinarenes

as Drug Solubilizing Agents Journal of

Nanomedicine

Research,

2015;

2(28).

without

compromising

efficacy.

its

and

https://doi.org/10.15406/jnmr.2015.02.00

028

antimycobacterial

Food

Chemical Toxicology, 2018; 119. 425–429.

https://doi.org/10.1016/j.fct.2017.12.022

[69]. Basilotta, R., Mannino, D., Filippone, A.,

Casili, G., Prestifilippo, A., Colarossi, L.,

Raciti, G., Esposito, E., Campolo, M. Role of

Calixarene in Chemotherapy Delivery

Strategies. Molecules, 2021; 26, 3963.

https://doi.org/10.3390/molecules261339

63

[77]. Li, B., Meng, Z., Li, Q., Huang, X., Kang, Z.,

Dong, H., Chen, J., Sun, J., Dong, Y., Li, J., Jia,

X., Sessler, J. L., Meng, Q & Li, C. A pH

responsive

delivery system for oxaliplatin. Chemical

Science, 2017; 8. 4458–4464.

complexation-based

drug

https://doi.org/10.1039/C7SC01438D

[78]. Geraci, C., Consoli, G. M. L., Giusappe, G.,

Galante, E., Palmigiano, A., Pappalardo, M.

S., Puma, S. D & Spadaro, A. The first self-

[70]. Nimse, S. B.,

&

T. Kim. Biological

applications of functionalized calixarenes.

Chemical Society Reviews, 2013; 42(1). 366-

386. https://doi.org/10.1039/C2CS35233H

[71]. Guo, D. S., & Y. Liu. Supramolecular

adjuvant

multicomponent

potential

vaccine candidates by tethering of four or

eight MUC1 antigenic immunodominant

PDTRP units on a calixarene platform:

Chemistry

of p-Sulfonatocalix[n]arenes

synthesis

and

biological

evaluation.

and Its Biological Applications. Accounts of

Chemical Research, 2014; 47(7) 1925.

https://doi.org/10.1021/ar500009g

Bioconjugate Chem, 2013; 24. 10. 1710–

1720. https://doi.org/10.1021/bc400242y

[79]. Ostos, F. J., J. A. Lebron, M. L. Moya, M.

Lopez, A. Sanchez, A. Clavero, C. B. Garcia-

Calderon, I. V. Rosado & P. L. Cornejo. P-

Sulfocalix[6]arene as Nanocarrier for

[72]. Ukhatskaya, E. V., S. V. Kurkov, S. E.

Matthews & T. Loftsson. Encapsulation of

Drug

Molecules

into

Calix[n]arene

Nanobaskets. Role of Aminocalix[n]arenes

in Biopharmaceutical Field. Journal of

Pharmaceutical Sciences, 2013; 102(10).

3485. https://doi.org/10.1002/jps.23681

[73]. Rodik, R. V., V. I. Boyko & V. I. Kalchenko.

Calixarenes in Bio-Medical Researches.

Current Medicinal Chemistry, 2009; 16(13),

1630-1655.

Controlled

Delivery

of

Doxorubicin.

Chemistry – An Asian Journal, 2017; 12. 6.

679-689.

https://doi.org/10.1002/asia.201601713 .

[80]. Zhao, Z.M., Wang. Y., Han, J., Zhu, H.D., An,

L. Preparation and Characterization of

Amphiphilic Calixarene Nanoparticles as

Delivery Carriers for Paclitaxel. Chemical &

Pharmaceutical Bulletin. 2015;63(3):180-

https://doi.org/10.2147/DDDT.S83213

[74]. Mokhtari,

Applications of calixarene nano-baskets in

pharmacology. Journal of Inclusion

Phenomena and Macrocyclic Chemistry,

2012; 73(1).

B

&

K.

Pourabdollah.

186.

00699

https://doi.org/10.1248/cpb.c14-

[81]. Mo, J., Eggers, P.K., Yuan, Z., Raston. C.L.,

Lim, L.Y. Paclitaxel-loaded phosphonated

calixarene nanovesicles as a modular drug

delivery platform. Scientific Reports, 2016;

https://doi.org/10.1007/s10847-011-0062-

z

6,

23489.

[75]. Bagnacani, V., V. Franceschi, M. Bassi, M.

Lomazzi, G. Donofrio, F. Sansone, A.

Casnati & R. Ungaro. Arginine clustering on

calix[4]arene macrocycles for improved

cell penetration and DNA delivery. Nature

https://doi.org/10.1038/srep23489 .

[82]. Yerga, L. G., I. Posadas, C. D. L. Torre, J. R.

Almansa, F. Sansone, C. O. Mellet, A.

Casnati, J. M. G. Fernandez & V. Cena.

Docetaxel-Loaded

Assembled from β-Cyclodextrin/Calixarene

Giant Surfactants: Physicochemical

Properties and Cytotoxic Effect in Prostate

Nanoparticles

Communications,

https://doi.org/10.1038/ncomms2721

2013;

4(1721).

164

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

Cancer and Glioblastoma Cells. Frontiers in

Pharmacology, 2017; 8: 249.

Interfaces,

2015;

7(21),

25946024.

https://doi.org/10.1021/acsami.5b02506

[89]. Zhang, T. X., Zhang, Z. Z., Yue, Y. X., Hu, X.

Y., Huang, F., Shi, L., Liu, Y & Guo, D. S. A

General Hypoxia-Responsive Molecular

Container for Tumor-Targeted Therapy.

Advanced Materials, 2020; 32(28), 1908435.

https://doi.org/10.1002/adma.201908435

[90]. Zyryanov, G. V., Kopchuk, D. S., Kovalev, I.

S., Santra, S., Majee, A & Ranu, B. C.

Pillararenes as Promising Carriers for Drug

Delivery. International Journal of Molecular

https://doi.org/10.3389/fphar.2017.00249

[83]. Mo, J., P. K. Eggers, X. Chen, M. R. H.

Ahamed, T. Becker, L. Y. Lim & C. L. Raston.

Shear induced carboplatin binding within

the cavity of a phospholipid mimic for

increased anticancer efficacy. Natural

Scentific.

https://doi.org/10.1038/srep10414

[84]. Renziehausen, A., A. D. Tsiailanis, R.

Reports,

2015;

5:10414.

P. Evgenios, K. Stylos, C. Chatzigiannis, K.

O'Neill, T. Crook, A. G. Tzakos, N. Syed.

2019. Encapsulation of Temozolomide in a

Calixarene Nanocapsule Improves Its

Stability and Enhances Its Therapeutic

Efficacy against Glioblastoma. Molecular

Cancer Therapeutics, 2019; 18 (9): 1497–

1505. https://doi.org/10.1158/1535-

Sciences,

2023;

24

(6),

5167.

https://doi.org/10.3390/ijms24065167

[91]. Ogoshi, T., S. Kanai, S. Fujinami, T. A.

Yamagishi & Y. Nakamoto. para-Bridged

Symmetrical Pillar[5]arenes: Their Lewis

Acid Catalyzed Synthesis and Host–Guest

Property. Journal of the American Chemical

7163.MCT-18-1250

Society,

2008;

130

(15)

5022.

[85]. Wang, Y. X., D. S. Guo, Y. C. Duan, Y. J. Wang

https://doi.org/10.1021/ja711260m

&

Y.

Sulfonatocalix[4]arene

Chaperone” for Escorting

Liu.

2015.

Amphiphilic

p-

[92]. Xue, M., Yang, Y., Chi, X., Zhang, Z & Huang,

F. Pillararenes, A New Class of Macrocycles

for Supramolecular Chemistry. Accounts of

Chemical Research, 2012 ; 45(8). 1294–1308.

https://doi.org/10.1021/ar2003418

as

“Drug

Anticancer

Drugs. Scientific Reports, 2015; 5, 9019.

https://doi.org/10.1038/srep09019 .

[86]. Sreedevi, P., Jyothi, B. N., Manu, M. J.,

Vishnu, P. M., Cherumuttathu, H. S., Varma

R. L., Kaustabh, K. M. Dynamic self-

assembly of mannosylated-calix[4]arene

[93]. Lu, B., Xia, J., Huang, Y & Yao, Y. The design

strategy for pillararene based active

targeted drug delivery systems. Chemical

Communications, 2023; 59 (81), 12091–

12099.

into

hydrophobic drugs. Journal of Controlled

Release, 2021; 339. 284-296.

micelles

for

the

delivery

of

https://doi.org/10.1039/D3CC04021F

[94]. Shangguan, L., Chen, Q., Shi, B & Huang, F.

Enhancing the solubility and bioactivity of

anticancer drug tamoxifen by water-

soluble. Chemical Communications, 2017;

https://doi.org/10.1016/j.jconrel.2021.09.0

38

[87]. Drakalska, E., Denitsa, M., Yana, M.,

Dessislava, B., Georgi, M., Margarita, G.,

Liudmil, A., Nikolay, L & Stanislav, R. Hybrid

liposomal PEGylated calix[4]arene systems

as drug delivery platforms for curcumin.

International Journal of Pharmaceutics.

53(70),

9749-9752.

https://doi.org/10.1039/C7CC05305C

[95]. Wheate, N. J., Dickson, K. A., Kim, R.R.,

Nematollahi, A., Macquart, R,B., Kayser, V.,

Yu, G., Church, W.B., & Marsh D.J. Host-

2014;

472(1-2),

165-174,

Guest

Complexes

of

Carboxylated

https://doi.org/10.1016/j.ijpharm.2014.06.

034

[88]. Bandela, A. K., V. K. Hinge, D. S. Yarramala

& C. P. Rao. Versatile, Reversible, and

Pillar[n]arenes With Drugs. Journal of

Pharmaceutical Sciences, 2016. 105. 3615.

https://doi.org/10.1016/j.xphs.2016.09.00

8

Reusable Gel of

a

Monocholesteryl

[96]. Sun, Y. L., Yang, Y. W., Chen, D. X., Wang, G.,

Zhou, Y., Wang, C. Y & Stoddart, J. F.

Mechanized silica nanoparticles based on

pillar [5]arenes for on-command cargo

Conjugated Calix[4]arene as Functional

Material to Store and Release Dyes and

Drugs Including Doxorubicin, Curcumin,

and Tocopherol. ACS Applied Materials &

165

M.F.N.Saputra et al.

Chempublish Journal, 9(1) 2025,141-166

release.

Small,

2013;9.3224–3229.x.

dimer

for

targeted

chemotherapy.

https://doi.org/10.1002/smll.201300445

[97]. Barbera, L., D. Franco, L. M. D. Plano, G.

Gattuso, S. P. P. Guglielmo, G. Lentini, N.

Manganaro, N. Marino, S. Pappalardo, M. F.

Parisi, F. Puntoriero, I. Pisagatti & A. Notti.

2017. Awater-soluble pillar[5]arene as a

new carrier for an old drug. Organic and

Biomolecular Chemistry, 2017;15, 3192-

3195. https://doi.org/10.1039/C7OB00530J

[98]. Jain, A., Prajapati, S.K., Kumari, A., Mody, N.,

Bajpai, M. Engineered nanosponges as

Chemical Communications, 2020, 56(73),

10642.https://doi.org/10.1039/D0CC04149

A

[102]. Silva, A. F. M. D., Nathalia, M. D. C., Tamires,

S. F., Isabela, A. A. B., Dayenny, L. D., Carlos,

A. S., Matheus, L. C., Vanessa, N., Antonio,

P. J., Braulio, S. A., Luis, F. R. P., Thiago, C. D

&

Celia,

M.

R.

2022.

Responsive

Supramolecular Devices Assembled from

Pillar[5]arene Nanogate and Mesoporous

Silica for Cargo Release. Applied Nano

Materials ACS, Mater, 2022; 5 (10), 13805–

13819.https://doi.org/10.1021/acsanm.2c0

1408

versatile

insight. Journal of Drug Delivery Science and

Technology, 2020; 57. 101643.

biodegradable

carriers:

An

https://doi.org/10.1016/j.jddst.2020.10164

3

[103]. Ding, C., Ying, L., Ting, W & Jiajun, F. Triple-

stimuli-responsive

nanocontainers

[99]. Yu, G., Dan, W., Yang, L., Zhihua, Z., Li, S.,

Jiong, Z., Qinglian, H., Guping, T & Feihei, H.

2016. A pillar[5]arene-based [2]rotaxane

lights up mitochondria. Chemical Science,

assembled by water-soluble pillar[5]arene-

based pseudorotaxanes for controlled

release. Journal of Materials Chemistry B,

2016;

4(16),

2819-2827.

2016,

7,

3017-3024.

https://doi.org/10.1039/C6TB00459H

https://doi.org/10.1039/C6SC00036C

[100]. Yang, K., Yincheng, C., Jia, W., Yuchao, L.,

Yuxin, P., Shoupeng, C., Feng, W & Zhichao,

P. Supramolecular Vesicles Based on

Complex of Trp-Modified Pillar[5]arene

and Galactose Derivative for Synergistic

and Targeted Drug Delivery. Chemistry of

[104]. Lan S,, Liu, Y., Shi, K & Ma, D. Acetal-

Functionalized

Pillar[5]arene:

A

pH-

Responsive and Versatile Nanomaterial for

the Delivery of Chemotherapeutic Agents.

ACS Appl Bio Mater. 2020;3(4):2325-2333.

https://doi.org/10.1021/acsabm.0c00086

[105]. Huang, X., Zhang, X., Qian, T., Ma, J., Cui, L

& Li, C. Synthesis of a water-soluble 2,2'-

Materials,

2016;

28(7).1990-1993.

https://doi.org/10.1021/acs.chemmater.6b

biphen[4]arene

and

its

efficient

00696

complexation and sensitive fluorescence

enhancement towards palmatine and

berberine. Beilstein Journal of Organic

[101]. Wang, Y., Ming, J., Zelong, C., Xianjun, H.,

Liang, P., Zhichao, P & Yuxin, P. 2020.

Tumor

supramolecular glyco-nanovesicles based

on diselenium-bridged pillar[5]arene

microenvironment

responsive

Chemistry,

https://doi.org/10.3762/bjoc.14.198

2018;

14:

2236-2241.

166