Vol 2, Issue 3, 2020 (124-131)

http://journal.unpad.ac.id/idjp

*Corresponding author,

e-mail : patihul.husni@unpad.ac.id (P. Husni)

https://doi.org/10.24198/idjp.v2i3.30026

Potential of Stimuli-Responsive Star Polymer for Cancer Targeting

Patihul Husni

1,2

*, M Alvien Ghifari

, Norisca Aliza Putriana

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas

Padjadjaran, Jatinangor 45363, Indonesia

Department of Global Innovative Drug, College of Pharmacy, Chung-Ang University, 221

Heukseok dong, Dongjak-gu, Seoul 06974, Korea

Department of Chemistry, Faculty of Science, Institut Teknologi Sumatera, Lampung Selatan,

35365, Indonesia

Received : 27 Okt 2020, Revised : 30 Nov 2020, Accepted : 3 Des 2020, Published : 10 Dec 2020

ABSTRACT

Application of stimuli-responsive star polymers in cancer targeting and drug delivery has

been extensively researched because of their several advantages in comparison with their

linear counterparts. Functionalization and recombination of various arm architectures of

the star polymer are very possible to be conducted to match with numerous needs. The

star polymers could not only load more therapeutic drug due to more arms than linear

polymers but also be functionalized with targeted moieties for more targeted delivery.

Furthermore, the chains in star polymers could be regulated to produce stimuli-responsive

star polymer for cancer targeting. This review article aimed to describe the benefits of

star polymers and the types of stimuli-responsive delivery system for cancer targeting.

Over the last decade, stimuli-responsive star polymers for cancer targeting using either

internal stimuli (e.g., pH, redox, enzyme, hypoxia) or external stimuli (e.g., thermal,

ultrasound, light, magnetic) has garnered immense interest for researchers. Possibility to

mimic a complex natural phenomenon could be achieved by incorporating various

stimuli-responsive functionalities in the star polymer.

Keywords: stimuli responsive; star polymer; cancer, drug delivery

1. Introduction

To date, cancer is still top trigger of the

global death. In 2018, cancer is responsible for

an estimated 9.6 million deaths (1). It is

predicted that > 20 million new cancer case

annually expected by 2025 (2). World Health

Organization (WHO) estimates the continue

rising of deaths to 11.5 million by 2030

worldwide (3). Cancer can spread into or

invade tissue. Cancer cell can spread or

invaded tissue by breaking off the cell and

travelling to other places through blood or

lymph system. As the result new tumors are

formed (4). Currently, researchers around the

world have put their effort to obtain newer and

more potent drug delivery systems (DDSs) to

treat cancer. The DDSs may overcome the

problem such as unfavorable biodistribution

and rapid clearance from the body (5). The

DDS should be designed to deliver cancer

drug to cancerous cells only and not to

surrounding healthy tissue. The concentration

of cancer drug must increase specifically at the

tumor site resulting in high treatment efficacy

with low side effects (5, 6).

Many DDSs have been developed to

target cancerous cells over the years. In

addition, many different strategies have been

evaluated such as passive targeting, active

targeting to cancer cells or endothelial cells

and triggered drug delivery (5). Effective

carriers are crucial to develop, to realize

successful therapies in cancer treatment. The

effectiveness of the carriers can be defined by

P. Husni et al / Indo J Pharm 3 (2020) 124-131

125

their nontoxicity, ability to carry anticancer

molecule, which targeted specific cells, and

combination therapy property (7). Using site-

specific DDSs, drug can achieve tumor in

therapeutic concentration for a continual

period of time with low systemic toxicity (8).

The targeted drug delivery is mainly used to

control the distribution of active molecule and

control delivery system based on polymer (7).

The use of DDSs based on polymer has been

widely investigated and many studies reported

the tailoring polymer architecture or

composition and evaluation the

physicochemical, in vitro and in vivo

properties of the polymers (9-13). In recent

years, polymeric materials have gained a lot of

attraction in DDSs due to its effectiveness in

cancer therapy (14-16). Advancement in

polymer engineering have led to the

fabrication of complex star polymer

architectures with unique properties and

applications that can be synthesized easily

(17).

Star polymers can be grouped into a

class of branched macromolecules with

adjustable several linear chains radiating from

a core (Figure 1). Many studies report

advantages of star polymers compared to

linear polymers (18-23).

Interestingly, the role of star polymers

in drug delivery and cancer targeting are that

(a) star polymers possess an ability to self-

assembled into a massive structure which can

be designed using their functionalizable arms.

This unique property cannot be met by the

simple linear polymer. In addition, (b) as their

designable architecture, modifying the arm to

control biodegradation rate is very possible.

Moreover, (c) star polymer can be

incorporated with stimuli responsive moiety

for DDSs and synthesized with certain

biomarkers to target cancer cells. The star

polymers mainly useful to deliver hydrophobic

molecules in aqueous environment (17). The

star polymers with more arms can not only

load more drug molecules than their linear

counterparts but also be functionalized with

targeted molecules for more targeted delivery

(18-21, 24, 25). In star polymers, the linear

branching chains can be chemically modulated

to fabricate stimuli-responsive materials (17).

Stimuli-responsive materials are ideal for

applications in drug DDSs to target cancer

cells because they are capable of automatically

undergoing conformational or chemical

changes upon receiving stimulus from the

environment (17). Some typical signals

include changes in pH, temperature, redox

trigger substance, enzyme, oxygen level

causing hypoxia, irradiation with light,

exposure to ultrasound or magnetic field (26).

The responses resulted by these stimuli are a

change in structural or shape, chain

conformation, solubility, surface activity,

color or transparency, increased permeability

to water, sol-gel transition and so forth (7, 26-

28). The stimuli-responsive functions facilitate

drug release to increase drug delivery

specificity, efficacy and biological activities

(26).

Application of stimuli-responsive star

polymers in cancer targeting and drug delivery

has been extensively studied by researcher.

For example, Li et al. prepared 4-armed star

copolymer of tetra-(methoxy-poly(ethylene

glycol)-poly(2-(N,N-diethylamino)ethyl

methacrylate)-poly(ε-caprolactone)

pentaerythritol as a pH-responsive nanocarrier

to deliver anticancer drugs for cancer targeting

(29).

Figure 1. Description of (a) star-shaped polymer, (b) star-shaped block copolymer, and (c) miktoarm

star polymer

P. Husni et al / Indo J Pharm 3 (2020) 124-131

126

In addition, redox-sensitive star polymer

consisted of poly(ε-caprolactone)-

poly(ethylene glycol) for targeted anticancer

drug delivery was synthesized by Shi et al

(30). Other researchers developed multi-

stimuli-responsive star polymer with more

than one responsive moiety for cancer

targeting using thermal and pH sensitive

material (31), light, pH and redox material

(32) or other combination of responsive

materials. In this review, we focus on the

benefits of star polymers and the types of

stimuli-responsive delivery system for cancer

targeting.

2. Benefits of Star Polymers

Linear polymers are non branched or

intramolecular bridges of polymer chain but

the structural unit is in a single line (33). In

contrast, star polymers are composed of

several linear chains which is linked to central

point or core (34) (Figure 1). In comparison to

linear chain polymer, the star structure offers

more advantages, such as those in Table 1.

Table 1. Benefits of star polymers.

Parameters

References

Lower critical micelle

concentration (CMC)

(18)

Higher stability

(18, 19)

Higher drug loading content

and drug loading efficiency

(18-21)

Smaller micelle size

(22, 23)

Smaller hydrodynamic

diameter

(21)

A CMC value is defined as parameter

related to micellization ability and stability of

micelle. The smaller CMC value, the stronger

the micelle-forming ability and micelle

stability. Original morphology of the micelle

can be retained by a lower CMC value of the

polymer until the micelles reach the target site.

Extreme dilution of the micelles can occur

when intravenous injection is given to human.

While the micelles circulate in the blood

stream below or above its CMC value, the

stable micelles have slower dissociation so it

can retain their integrity and drug content (35).

A low CMC value of star polymers can be

attributed to the hydrophobic interaction of the

polymer and the length of the hydrophobic

segments (36). The specific benefit of the low

CMC value of the star polymer on the delivery

system for cancer targeting is that a low CMC

value of the polymer may achieve greater

accumulation in the cancer cells because a

lower CMC value indicates improved structure

stability during systemic circulation until the

carrier reach the cancer cells (37).

Stability of star polymer-based

unimolecular micelles is higher than micelles

from amphiphilic molecules due to covalently

fixed branching points of unimolecular

micelles (the lipophilic components are

covalently bound together) (35, 38). In

addition, the main reason probably is that the

star polymers have intrinsic core-shell

structures and the hyperbranched core

structures plays a role to reduce the risk of

micellar disassembly effectively (18).

Polymer architecture greatly influences

drug encapsulation. This drug encapsulation is

affected by solvent type, concentration and

duration when loading drugs process. The

drug encapsulation mainly depends on the

affinity of intrinsic interaction between drug

and certain groups of hydrophobic segment

(35). Higher drug loading of poorly water

soluble or hydrophobic drug is caused by the

increased or higher hydrophobicity of polymer

block (39, 40). The star polymers provide

large cavities to load more hydrophobic drug

(18). Moreover, increasing the length of

polymer chain and subsequently the molar

mass of star polymers have substantial effect

on material’s loading capabilities (20). Star

polymers have more arms which able to carry

more drug molecules than linear polymers

(19).

The micelle size is also critical factor for

drug delivery. Delivery systems that are

smaller than 200 nm provide long circulation

time of micelles in the blood, reduce uptake by

the reticuloendothelial system (RES), and

facilitate the extravasation at leaky site of

capillaries. Renal elimination can be prevented

if the micelles have high molecular weight (>

g/mol). Meanwhile, supramolecular

structures often accumulate in the spleen and

P. Husni et al / Indo J Pharm 3 (2020) 124-131

127

liver because of their large size or protein

adsorption which trigger rapid uptake by RES

(35). Star polymers have smaller micelle size

than for linear copolymer due to the more

compact nature of star polymers (41).

The constrained geometry architecture

and the molecular interactions among the star

polymers lead to a smaller hydrodynamic

volume. The smaller hydrodynamic size will

have higher cellular uptake efficiency (21).

3. Types of Stimuli Responsive Delivery

System for Cancer Targeting

The role of stimuli-based delivery

system is a critical point in DDSs because of

the environmental variation in cancer cells.

Interestingly, responsive materials are able to

mimic some biological processes and

recognize at the molecular level to manipulate

development of custom-designed molecules to

increase the specificity of cancer drug delivery

and for targeting cancer cells (26, 42). The

responsive materials respond to different

stimuli or changes in the environment (7).

Stimuli-responsive DDSs for cancer targeting

divide into external stimuli and internal

stimuli (Figure 2). In case of internal stimuli,

the internal triggers are intrinsically existed in

tumor microenvironment or inside cancer

cells. In contrast to internal stimuli, externally

triggers are applied outer of tumor or cancer

cells when the external stimuli method is used

(26).

Internal stimuli can be categorized as

pH, redox, enzyme, and hypoxia. pH-

responsive polymers contain weakly acidic or

basic ionizable groups (pKa values 3 - 10)

which either donate or accept protons in

response to changes in environmental pH. A

change in ionization state as function of pH

resulted alteration in structural and other

properties (chain conformation, solubility,

surface activity, etc.) is demonstrated by the

acidic or basic groups of polyelectrolytes

(carboxylate, sulfonate, and amino groups).

The pH-responsive polymers have different

characteristic under a neutral and acidic or

basic condition. Electrostatic repulsion occurs

between charged groups as a result an increase

in degree of ionization (7). In case of redox-

responsive delivery system, the glutathione

(GSH) level inside cancer cells (2-10 mM) is

remarkable higher than that in normal regions

(2-10 µM) (26). Hence, the GSH presence in

higher concentration within tumor or the

microenvironment of the cancer cells. The

GSH acts as a trigger for the reduction of the

disulfide bond (SS) linkage. The redox-

responsive function could trigger the

dissociation and degradation carriers inside

cancer cells (30). Enzyme-

Figure 2. Description of types of stimuli-responsive DDSs used for cancer targeting

P. Husni et al / Indo J Pharm 3 (2020) 124-131

128

responsive delivery systems are based on the

response to several upregulated enzymes in

tumor microenvironment and cancer cells

(26). There is a changed articulation of

catalyst induced by enzyme observed in

cancer cells (42). Over-expression of enzymes

by tumor cells is resulted for tumor growth,

angiogenesis, invasion and metastasis (43). In

relation to hypoxia-responsive delivery

system, hypoxia could trigger cargo release

from the hypoxia-sensitive carriers due to the

cleavage of hypoxia-sensitive cross-linkers.

Tumor hypoxia (low oxygen level) is likely

caused by poorly vascularization inside solid

tumors (26). An over consumption of oxygen

by rapidly proliferating cells of tumor results

in tumor hypoxia and also due to inconsistent

flux of erythrocyte in the abnormal tumor

vasculature (43).

External stimuli can be triggered by

thermal, ultrasound, light and magnetic.

Thermal-triggered delivery systems are

generally designed to change significantly in

their properties by responding to the narrow

temperature shift. The thermal-responsive

carriers are stable in temperature up to 37

and sensitive to higher temperature (> 40

for achieving thermal-triggered drug release

and therapy (26). To utilize the ultrasound, a

high frequency sound waves are needed. The

sound wave above 20 kHz are applied either to

disrupt carrier to release the cargo or enhance

the cell membrane’s permeability. Other than

that, the light irradiation (UV-Vis and near-

infrared light) generally could remotely affect

the light-responsive carriers in cancer cells

(26). The optical signal induces the

photochromic molecule (chromophores) in the

photoreceptor to convert the light-irradiation

into a chemical signal by photoreaction

process. For magnetic-responsive delivery

system, generally, strategy used in developing

magnetic-responsive delivery system is either

incorporating magnetic materials into carriers

for achieving magnetic-sensitivity or locating

a permanent magnetic field in malignant tissue

after administration.

Majority of the delivery system based

on stimuli-responsive deals with response to a

single stimulus. However, biological

performance of macromolecules shows

changes in response to a combination of

stimuli. In order to mimic biological

processes, different stimuli-responsive

functionalities can be incorporated in a single

polymer to create multi-stimuli-responsive

materials to provide more than one mechanism

responsiveness for targeting cancer cells (26,

42). Star polymer for drug delivery to cancer

targeting seems to be important candidate

because of their unique properties.

4. Conclusion

Stimuli-responsive materials have

received increasing interest in recent years,

due to its unique properties. The star polymers

can load more drug molecules and be

functionalized with targeted molecules for

more targeted delivery. The responsive

materials respond to different stimuli or

changes in the cancer environment. Until now,

numerous internal and external stimuli-

responsive star polymers have been developed

to mimic some biological processes, recognize

at molecular level and facilitate drug release to

increase drug delivery specificity, efficacy and

biological activities for cancer targeting.

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