Journal of Macromolecular Science, Part A

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Polycaprolactone: a biodegradable polymer with

its application in the field of self-assembly study

Piyali Mandal & Raja Shunmugam

To cite this article: Piyali Mandal & Raja Shunmugam (2021) Polycaprolactone: a biodegradable
polymer with its application in the field of self-assembly study, Journal of Macromolecular Science,
Part A, 58:2, 111-129, DOI: 10.1080/10601325.2020.1831392

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JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY
2021, VOL. 58, NO. 2, 111–129
https://doi.org/10.1080/10601325.2020.1831392

Polycaprolactone: a biodegradable polymer with its application in the field of

self-assembly study
Piyali Mandal and Raja Shunmugam
Polymer Research Centre, Department of Chemical Sciences and Centre for Advanced Functional Materials, Indian Institute of Science
Education and Research Kolkata, Mohanpur, West Bengal, India

ABSTRACT ARTICLE HISTORY

Synthetic polyesters have created a considerable attraction among the researchers over a few dec- Received July 2020
ades. Among them, polycaprolactone (PCL) is of great interest since the 1970s-1980s in various sci- Accepted September 2020
entific and industrial fields. This particular aliphatic polyester is unique by its biocompatibility,
KEYWORDS
biodegradability, physicochemical and mechanical properties. It can be synthesized through poly-
Anti-cancer drug;
condensation and ring-opening polymerization techniques. PCL moiety is hydrophobic and cap- caprolactone; polymer; self-
able of aggregates formation (through self-assembly behavior) after combining with a hydrophilic assembly; stimuli-responsive
entity. These aggregates can form sophisticated architectures of huge biomedical applications.
Here, in this critical review, we have thoroughly discussed the synthesis, physical and biological
properties of PCL and their connectivity with the self-assembly behavior. We have mainly focused
on its applications in the field of controlled drug release and tissue engineering.

GRAPHICAL ABSTRACT

1. Introduction ester and achiral. This is a colorless liquid. It can be synthesized

1.1. Caprolactone: the monomer
Caprolactone (CL) is a cyclic ester, possessing a seven-mem-
bered ring. The word caprolactone is derived from the word
caproic acid. Generally, e-CL is known as caprolactone
which is commercially available. Several other isomers of CL
(-a, -b, -c, -d,) are also known. According to their stereo-
chemistry, caprolactones are chiral in nature. (R)-c-CL can
be found as a component of floral scents and aromas of
some fruits and vegetables[1] and d-CL is being found in
heated milk fat.[2] Among these isomers, e-CL is a synthetic
in several ways but the most useful and cost-effective route is
the Baeyer-Villiger oxidation of cyclohexanone (Figure 1).[3–4]
Among these aforementioned isomers, e-CL can be easily poly-
merized and thus its mechanical properties can be fine-tuned
leading to its enormous use in the field of applied chemistry.
1.2. Polycaprolactone: the polymer
1.2.1. Synthesis
Polycaprolactone (PCL) is aliphatic polyester. There are two
main pathways to produce this polymer.

CONTACT Raja Shunmugam sraja@iiserkol.ac.in Polymer Research Centre, Department of Chemical Sciences and Centre for Advanced Functional
Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India.
ß 2020 Taylor & Francis Group, LLC
112 P. MANDAL AND R. SHUNMUGAM
Figure 1. General synthesis of the caprolactone monomer.
I. Polycondensation and
II. Ring-opening polymerization.
Now a day, (III) green synthesis is also popular among sci-
entists to minimize the chemical hazards in the environment.
PCL can also be produced by adopting that methodology.
I. Polycondensation:
Generally, 6-hydroxycarboxylic acids and diols take part
to produce polyesters.[5–6] Braud et al.[7] synthesized PCL
using 6-hydroxy-hexanoic acid as the precursor. This reac-
tion was done within 6 h without involving any catalyst at a
wide range of temperature from 80-150
C. Gross et al.[8]
used 6-hydroxycaproic acid and lipase from Candida
Antarctica to obtain PCL and the process has taken 2 days.
Shen et al.[9] have taken the lipase from Pseudomonas sp.
and the reaction time increased to 20 days. Chu et al.[10]
synthesized amino acid-derived PCL by solution polycon-
densation at 45
C temperature within 48 h using dimethyla-
cetamide (DMA) as a solvent. Enough number of patents
also described the PCL synthesis by polycondensation.[11–14]
There are few drawbacks of polycondensation reactions:
i. Prolonged reaction times.
ii. High reaction temperature.
iii. Removal of by-products.
iv. Lack of precise stoichiometric balance.
v. Production of low molecular weight polymers with a
broad polydispersity.
(II) Ring-opening polymerization:
Ring-opening polymerization (ROP) is a form of chain-
growth polymerization. Carothers and coworkers were the
first group to explore ROP. PCL was first synthesized by
ROP in the 1930s.[15] ROP follows the pathway via alkyl-
oxygen or acyl-oxygen scission. Generally, ROP can be div-
ided into four categories:
(a) Anionic ring-opening polymerization:
Here, the polymerization occurs via formation of anionic
species. Next, the anion attacks the carbonyl carbon of the
caprolactone monomer. As a consequence, acyl-oxygen bond
opens and an alkoxide moiety generates as intermedi-
ate.[16–17] Intramolecular transesterification, also called as
“back-biting”, is a relevant side reaction phenomenon in this
process and it lowers the molecular weight of the synthe-
sized polymers. This is a drawback of this technique.
(b) Cationic ring-opening polymerization:
Cationic ROP follows the nucleophilic substitution (SN2)
pathway. It involves the formation of a cationic species
which is further attacked by the carbonyl oxygen of the cap-
rolactone monomer. This can be found in the presence of
Lewis acids.[18]
(c) Monomer-activated ring-opening polymerization:
This process involves the activation of the caprolactone
monomer by a catalyst, followed by the attack at the poly-
mer chain by that activated monomer.[19]
(d) Coordination-insertion ring-opening polymerization:
Here the coordination between monomer and a metal cata-
lyst occurred followed by the insertion of metal into the
metal-oxygen bond of the catalyst i.e.; an alkoxide bond for-
mation takes place in this step.[20] This can be called as
pseudo-anionic ROP.
The main drawback of ROP is intramolecular and inter-
molecular trans-esterification. In both cases, side reactions
take place, resulting in the broadening of polydispersity.[21–22]
The mechanism for (a) anionic ROP, (b) cationic ROP,
(c) monomer-activated ROP and (d) coordination-insertion
ROP of e-caprolactone have been sketched in Figure 2.[23]
(III) Green synthesis of PCL:
Green synthesis of PCL involves environmentally safe
and clean synthetic procedures. Several green approaches
were followed to synthesize PCL to date. Sachs et al.[24]
reported PCL synthesis by adopting green chemistry. They
used a different ratio of e-CL and iodine and stirred at
room temperature for 72 h, followed by the precipitation in
cold methanol. After that, they removed the iodine using
sodium thiosulfate. Baudry et al.[25] reported microwave
mediated PCL formation in terms of green synthesis.
Among all the techniques, coordination-insertion ROP is
the most common, appropriate and convenient procedure
which is applied for the polymerization of e- caprolactone.
The PCLs thus obtained possess high molecular weights
with narrow polydispersity indices.
1.2.2. Catalysts used for ring-opening polymerization of
e-caprolactone
Catalysts play a crucial role in the case of ROP. It is typic-
ally needed to activate the carbonyl moiety of the lactone
monomer. By regenerating themselves in the termination
step, it keeps the polymer chain “alive” to obtain high
molecular weight. Few important catalysts are mentioned in
Table 1 as commonly used in ROP of e-CL.
Among the metal catalysts, aluminum and tin-based com-
plexes are highly effective and frequently used. But, organ cat-
alysts are of great interest for the sake of easy removal just
after the reaction. It can be removed by easy washing with
organic solvents. The mechanism for ROP of e-CL with DPP
(Diphenyl phosphate) catalyst has been depicted in Figure 3.
1.3. Molecular architectures
In recent years, different mechanisms have been developed
for controlled polymerization of cyclic esters. Some
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY
Figure 2. Mechanism of different ROP techniques for e-caprolactone.
interesting architectures may be produced as a result of
these versatile strategies (Figure 4). Depending on the struc-
tural factors, classification of PCL results in following
categories:[47]
(I) Linear
Linear structure for a polycaprolactone molecule can be
termed as a telechelic polymer or oligomer. It is having
reactive end groups, where both the ends possess the same
functionality.[48–49] This prepolymer can take part in further
polymerization through its end groups. Generally, it is a
result of step-growth polymerization.
(II) Branched
These polymers are having side chain or secondary poly-
mer chains with the main backbone. These branches are
made up of the same repeating unit and it results from side
reactions during polymerization.[50] It can be comb-shaped,
star-shaped and miktoarm star-shaped. Dendrimers are also
a type of branched polymers.
(III) Cross-linked
In cross-linked architecture, the monomer units are
cross-linked into a three-dimensional polymer network
through the bond formation.[51] It is insoluble. Here, poly-
mers chains are tied with a very strong covalent bond.
113
(IV) Supramolecular
Supramolecular structures for polycaprolactone are gener-
ally formed due to the self-assembly of amphiphilic mole-
cules. Here PCL is hydrophobic and the counterpart should
be hydrophilic. The two most important architectures are
micelles and vesicles (Figure 5).
(a) Micelle
Micelle is an aggregate of amphiphilic molecules, consists
of a hydrophilic head and a hydrophobic tail. That is dis-
persed in a colloid liquid, typically in aqueous solution. It
exhibits a core-shell type structure and the hydrophobic tails
result in core formation.
In a non-polar solvent, the hydrophilic heads are seques-
tered toward the core and hydrophobic tails are extended
away from the center, then the aggregates are termed as
reverse or inverse micelle.
The molecular weight of monomer, aggregation number
and hydrophobic-hydrophilic ratio are the main governing
factors for micelle formation.[52]
(b) Vesicle
The vesicle is also an aggregate composed of amphiphilic
molecule in colloid liquid but the structure is like a typical
bilayer. The formation of this architecture depends on polymer
chain length, solubility and glass transition temperature.[53]
114 P. MANDAL AND R. SHUNMUGAM

Table 1. Few catalysts, which are using for polycaprolactone synthesis.

Entry Catalyst Solvent T(
C) Time Conv. Mn(g/mol) PDI Ref.
Alkali-based catalysts
1 Lithium diisopropylamide Dioxane 25 5 min 100 5700 – [26]

2 Cyclopentadienyl sodium Toluene 20 1h 98 11600 – [27]

3 Potassium tert-butoxide scCO2 (155 bar) 108 15 – 6000 2 [28]

Alkaline earth-based catalysts

[29]
4 Magnesium aryloxide Toluene 110 12 h 99 54200 1.35
[30]
5 Calcium 4-Nitrophenethoxide Toluene 70 12 h 87.2 2400 1.20
[31]
6 Strontium isopropoxide Toluene 41 2h 100 30300 1.85
Poor metal-based catalysts
[32]
7 Aluminum isopropoxide DCM RT 18 h 80 49790 1.21
[33]
8 Tin(II) octoate Toluene 80 48 h 95 73000 1.28
Transition metal-based catalysts
9 Titanium alkoxide Toluene RT 24 h – 8500 2.60 [34]

10 Vanadium sulfate Methanol 60 24 h 99 – – [35]

[36]
11 Iron(III) alkoxide Toluene 25 16 h 100 36400 1.20
[37]
12 Copper triflate None 60 24 h 86 16400 1.97
[38]
13 Diethylzinc/GA None 40 48 h 72 7900 1.78
[39]
14 Zirconium(IV) acetylacetonate Benzene 80 10 h 95 6600 1.5
15 Molibdinum(V) acetylacetonate Methanol 60 24 h 99 – – [35]

16 Hafnium-amide complex Toluene 25 – – 52962 1.45 [40]

Rare earth metal-based catalysts

[41]
17 Scandium trifluoromethanesulphonate Toluene 35 21 h 98 6100 1.16
[42]
18 Yttrium tris(isopropoxide) DCM 22 5 min 100 6000 1.14
19 Lanthanum isopropoxide Toluene 110 7 min – 16500 1.5 [28]

20 Cerium triflate Toluene 25 8.5 h – 1800 1.21 [43]

[44]
21 Neodynium isopropoxide Toluene 50 10 h 100 1550 1.1
[44]
22 Samarium isopropoxide Toluene 50 5h 100 1100 1.9
23 Europium triflate Toluene 25 114 h – 1700 1.22 [43]

24 Gadolinium triflate Toluene 25 120 h – 1600 1.17 [43]

25 Ytterbium triflate Toluene 25 30 h – 1700 1.23 [43]

26 Lutetium triflate Toluene 25 91 h – 2200 1.30 [43]

Metal-free/ Organic catalysts

[45]
27 Diphenyl phosphate Toluene RT 24 h 86.6 11500 1.07
[46]
28 1,5,7-Triazabicyclo None 80 1h 99 12000 1.39
[4.4.0] dec-5-ene
[46]
29 1,8-diazabicyclo(5.4.0) None 80 72 h 99 13100 1.49
undec-7-ene
T ¼ Temperature, Conv. ¼ Conversion, Mn¼ Number Average Molecular Weight, PDI ¼ Polydispersity index, Ref. ¼ Reference, DCM ¼ Dichloromethane,
RT ¼ Room Temperature, GA ¼ Galic Acid.

Figure 3. Mechanism for ROP of e-CL with DPP catalyst.

1.4. Properties
Polycaprolactone is a semi-crystalline polymer because of its
regular structure with melting point range from 59
C to
64
C and low glass transition temperature at 60
C.[54]
This polymer is tough as well as flexible.[55] It exhibits a
rubbery state with high permeability of low molecular sub-
stances to body temperature. PCL is soluble in a wide range
of solvent at room temperature such as dichloromethane,
chloroform, tetrahydrofuran, benzene, carbon tetrachloride,
toluene, cyclohexanone etc. It is having low solubility in
acetone, dimethylformamide, ethyl acetate, acetonitrile and
insoluble in ether and alcohol.[56] The physical, chemical
and mechanical properties of PCL can be modified effi-
ciently by copolymerization and blending.[57] It has been
observed that blending alters the physical and mechanical
properties along with biodegradation. For example, the
blending of PCL with polylactide decreases Young’s modulus
and tensile strength whereas; PCL/cellulose composites can
increase crystallinity and crystalline temperature. The blend-
ing of PCL and proteins reduce the water susceptibility and
increase the stability in ambient conditions to the plastics
made from protein alone. Furthermore, copolymerization
leads to alter chemical properties which can indirectly influ-
ence other properties like solubility, crystallinity and degrad-
ation pattern. Several natural polymers (chitosan, starch,
hydroxyl appetite) andsynthetic polymers (polyurethane
(PU), polyethylene glycol (PEG), oxazolines, polyvinyl
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY 115

Figure 4. Representative polymeric architectures of PCL (red segments denotes the PCL chains).

Figure 5. Supramolecular architectures composed of PCL moiety (red segments denote the PCL chains).

Figure 6. Schematic illustration of the degradation pathway for PCL and its elimination from the body via citric acid cycle.

alcohol (PVA), polyethylene oxide (PEO), polylactic-co-gly- systems, copolymerization of PCL with any hydrophilic seg-
colic acid (PLGA) and polylactic acid) are found to be com- ment (e.g. PEO, PEG etc.) produces an amphiphilic moiety
patible with polycaprolactone which can modify the thermal, and introduction of NIPAM like moiety makes the whole
rheological and biophysical properties.[58] In drug delivery entity thermoresponsive.
116 P. MANDAL AND R. SHUNMUGAM
Figure 7. Graphical illustration of the complete degradation of PCL with respect
to time.
1.5. Biodegradability
The degradation time of polycaprolactone depends on
molecular weight, pore size, degree of crystallinity and
morphology.[59] PCL degradation starts with amorphous
phases followed by the crystalline domains. The degree of
crystallinity increases with increasing the degradation which
indicates the preferential degradation takes place in the
amorphous region. This procedure can be termed as a two-
stage degradation process. Firstly, hydrolytic cleavage of
ester linkage takes place in physiological conditions (prefer-
ably at 40
C)yielding 6-hydroxycaproic acid with an inter-
mediate of x-oxidation and b-oxidation to acetyl-SCoA
which then enters the citric acid cycle to be metabolized
completely (Figure 6).
This process is self-catalyzed and it follows first-order
reaction kinetics. Next, the crystalline part degrades by liv-
ing organisms like bacteria and fungi[60–62] in different
biotic environments like lake water, soil, sewage sludge,
river, farm soil, paddy soil, creek sediment, roadside sedi-
ment, pond sediment, compost and abiotically in phosphate
buffer solutions.[63–64] Particularly, esterase and some kind
of lipase enzymes play the role behind this phenomenon.
The low molecular weight polymer can be degraded by
Aurebasidium (Pullularia) pullulans but for high molecular
weight, its effect is negligible. For high molar mass,
Penicillium sp. strain and yeast play a significant role to
degrade that polymers. Degradation rate does not depend
on the shape i.e.; whether it is a film or microparticle rather
recycling and addition of processing additives reduce the
degradation rate. The degradation caused by biotic environ-
ments was higher than the abiotic environments due to syn-
ergism between high temperature and a richer fauna of
microorganisms. The radiation-cross-linked polycaprolac-
tone degrades slowly using lipase enzyme at pH 7 than that
of uncross-linked polycaprolactone due to their network
structure. Depending upon the architecture, usually, the
PCL homopolymers take overall 2 to 4 years for complete
degradation.
The biodegradation of polycaprolactone occurs through
surface or bulk degradation pathways. Surface erosion
involves the hydrolytic cleavage only at the surface.[65] This
process occurs only if the rate of surface erosion exceeds the
rate of hydrolytic intrusion to the bulk polymer or the rate
of production of oligomers and monomer.[66] This mechan-
ism is highly appreciable in the field of drug delivery as the
rate of drug release can be tailored by the surface modifica-
tion of the polymer device. The surface erosion mechanism
can lead to zero-order drug release kinetics. The whole deg-
radation process of PCL can be illustrated graphically in
Figure 7.[67]
2. Application
The caprolactone polymer is extensively used in the field of
biomedical application along with the other industries like
packaging, reinforced composites, etc. because of its unique
physical, chemical, mechanical properties and processibility.
To the best of our knowledge, it is mainly applied in the
pharmaceutical and biomedical fields.
2.1. Pharmaceutical and biomedical applications
PCL is widely explored in drug delivery study, tissue engin-
eering, medical devices and many other biomedical areas
due to its advantageous characteristics like biodegradability,
biocompatibility and cost-effectiveness. Here, we will mainly
focus on the self-assembly based application of polycaprolac-
tone, where amphiphilicity plays the key role. Self-assembled
polymeric micelles from amphiphilic copolymer have drawn
great attention due to several advantages like; prolong circu-
lation, the better water solubility of lipophilic drugs, decreas-
ing side effects and targeted delivery via EPR (enhanced
permeability and retention) effect. Application wise these
can be pointed out as:
I. Delivery application and
II. Tissue engineering
(I) Drug delivery application
Among the biodegradable polyesters, the PCL motif is of
great interest not only for their biodegradable and biocom-
patible nature but also for its large variety of degradation
properties. By tuning the degradation time, one can alter the
pharmaceutical dosage.[68] The slow degradation rate of PCL
facilitates long-term drug release upto several months[69]
and the rate can be tuned upto 1 year by physical or chem-
ical modification.[70] The biocompatibility of this polymer
enables the uniform distribution of an enormous number of
drug molecules along with the matrix.[71] Polycaprolactone
is highly permeable to small drug molecules which can be
fully excreted from the body once it is bioresorbed[72] and it
generates a very negligible acidic environment during the
degradation phenomenon.
But the main constraint is the poor water solubility of
the caprolactone homopolymers. To resolve the problem,
amphiphilicity can be incorporated into the polymer by
introducing hydrophilic moiety and the whole entity will be
able to dissolve in water via self-assembly. This process can
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY
Figure 8. Overall self-assembly and drug release process for TBA-PCL.
be done in two ways; either by nanosphere/microsphereor
by electrospun mats formation.
 Delivery application by nanosphere/microsphere formation
When the caprolactone homopolymers (with the hydro-
philic entity) or copolymers (amphiphilic) are subjected to
the aqueous solution then it usually forms nanoaggregates;
where the core is made up with hydrophobic PCL unit along
with hydrophilic corona units. Here the core serves as a res-
ervoir for drug molecules. Depending upon the properties,
drugs can be incorporated via chemical, physical or electro-
static interactions.[73–74]
Generally, PCL based amphiphilic copolymers take part
in the formation of the aggregates adopting the morpholo-
gies like micelle, vesicles, etc. There are very few examples
available for PCL based amphiphilic homopolymers which
can be further used as a delivery vehicle. Shunmugam
et al.[75] reported the doxorubicin drug delivery vehicle
which is composed of thiobarbiturate based polycaprolac-
tone (TBA-PCL). Here, the thiobarbiturate is only responsi-
blemoiety for hydrophilicity which makes the whole
molecule amphiphilic, and also it formed hierarchical super-
structures via hydrogen bonding (Figure 8). The anticancer
drug doxorubicin was encapsulated inside the hydrophobic
PCL core. It can be released in a sustained manner under
external stimuli like acidic pH and polarity change which
can break the hydrogen bonding as well as disrupts
the aggregates.
As we know the slow degradation characteristics of PCL,
Jeong et al.[76] have tuned that to a fast degradable one by
attaching oxalate functionality with the backbone. On the
other hand, the release profile remains slower than the other
polyesters. The entity adopts spherical morphology in aque-
ous solution and this was used to deliver the anti-cancer
drug, paclitaxel (PTX) into the subcutaneous layer of rats.
Here the oxalate bond was preferentially cleaved in the pres-
ence of reactive oxygen species (ROS), which may accelerate
the drug release.
Poly(ethylene glycol) i.e. PEG is a great choice to over-
come the water solubility issue of caprolactone. PEG is flex-
ible, nontoxic, hydrophilic, biocompatible and can act as a
protein stabilizer and surface modifier.[77] It is feasible to
117
make PCL copolymer via ROP by using PEG as an initiator.
The copolymer will be able to form nanoaggregates where
hydrophobic drug molecules can be encapsulated into the
core. Otherwise, a drug like cisplatin which requires chela-
tion can be directly anchored to the polymer backbone via
carboxylic acid functionality.[78] Here the drug release
phenomenon is pH controlled. The first example of a pH-
responsive dual drug delivery vehicle, under the gastrointes-
tinal tract, composed of carboxylic functionalized polycapro-
lactone block copolymer vesicles was reported by
Jayakannan et al.[79] The drugs thus produced can be
administered orally. The vesicles are capable of loading
hydrophilic drug (Rhodamine B) in the core and hydropho-
bic drug (ibuprofen and camptothecin) in the layers. These
vesicles release the loaded drugs in neutral or basic pH
(similar to the small intestine) while it is stable in strong
acidic (<pH 2.0, stomach) condition (Figure 9). In vitro
release study ensures the release of drug molecules occurs
exclusively under simulated interstitial fluid (SIF) which is
identical to our small intestine environment.
Furthermore, the PEG-PCL copolymer can be decorated
with galactose moiety or carbamic acid benzyl ester (CAB)
functionality for loading PTX and doxorubicin (DOX) drug
respectively. The galactose conjugated copolymers enhance
hepatoma targeting delivery of PTX and it has great chemo-
therapeutic potential toward the liver.[80] Here the copoly-
mers were cross-linked under UV radiation to afford the
micelles for loading of PTX. On the other hand, CAB is
enhancing the stability of micelles along with a significant
decrease of critical micelle concentration (CMC). It reduces
the crystallinity of the core and makes easy solubilization of
hydrophobic drugs. The interaction between the core-form-
ing block and drug molecules remains non-covalent.
Moreover, the drug delivery system (DDS) exhibits lower
cytotoxicity due to the slow release of the encapsulated
drug.[81] ABA type triblock copolymer of PEG-PCL also act-
sas DDS where incorporation of acetal linkage makes the
systemsignificantly responsible toward pH stimuli.[82–84] To
deliver a high molecular weight, negatively charged drugs,
like enoxaparin, which has low permeability through the
biological membrane, Junyaprasert et al.[85] developed a cat-
ionic triblock copolymer. Propargyltrimethyl ammonium
iodide was used as cationic ligand, which increases
118 P. MANDAL AND R. SHUNMUGAM
Figure 9. Carboxylic substituted PCL block copolymer vesicles and their pH stimuli response delivery under the GI tract. (Reproduced with permission from ref.[79]
Copyright 2013, American Chemical Society).
Figure 10. Chemical structure of PEG-SS-PCL-DOX.
encapsulation efficiency by 90%. The release profile is pH-
dependent where the micelle protects the drug in the acidic
environment with a possible release in blood circulation.
Along with the pH-responsive functionality, further intro-
duction of biotin or folic acid makes the copolymer as the
cancer cell-targeted delivery device also. As cancer cell
exhibits higher biotin content than normal tissue, so it can
be used as targeting ligand.[86] Similarly, the surfaces of can-
cer cells are frequently overexpressed with the folate recep-
tor.[87–88] Kissel et al.[89–90] developed a folate conjugated
ternary copolymer, for efficient tumor-targeted gene and
siRNA delivery, composed of polyethyleneimine-graft-poly-
caprolactone-block-poly(ethyleneglycol)-folate. Here, polye-
thyleneimine was used as a polycation which condenses
nucleic acids. PCL forms the hydrophobic coreto load
hydrophobic drug and PEG is the hydrophilic as well as bio-
compatible moiety which confirms prolong circulation with
cancer cell-targeted folate receptor.
As the cancer cells exhibit elevated glutathione (GSH), so
the mode of anti-cancer drug release can be fabricated with
redox responsive functionality.[91] Usually, a disulfide link-
age gets incorporated into the copolymers which make the
nano-vehicle stable in circulation but may cleave at intracel-
lular region due to the high concentration of GSH. A star
polymer was synthesized by Li et al.[92] with PEG-PCL and
dipentaerythritol moiety, where 3,3-dithiodipropionic acid
was used as a di-sulfide source. Next, the DOX drug was
encapsulated via the dialysis method to be applied to MCF-7
cancer cells. Shunmugam et al.[93] also reported a multi
stimuli-responsive copolymer (PEG-SS-PCL-DOX) where
DOX was covalently attached to the polymer backbone via
pH-sensitive acylhyrazine linkage (Figure 10). 2-hydrox-
yethyl disulfide provides the redox responsive S-S moiety
where PEG functionality comes up withthe amphiphilic
environment and the copolymer aggregates like vesicles in
aqueous solution. Cystamine moiety is another disulfide
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY
Figure 11. Schematic representation of PEG-PCL-based DHBCs and illustration of their pH-responsive self-assemblies (Reproduced with the permission from ref.[108]
Copyright 2020, American Chemical Society).
linkage provider to make the copolymer as redox respon-
sive vehicle.[94]
Peptides can target a few cancer cells. Some specified
peptides are available as metastatic tumor-targeted vehicles.
A cyclic ten-amino acid peptide is referred to as tumor
metastasis targeting (TMT) peptide. Dinarvand et al.[95]
reported such kind of TMT conjugated PEG-PCL copolymer
for targeted delivery of carbazitaxel to metastatic breast can-
cer cells. The copolymer was synthesized via amidation reac-
tion and TMT was covalently conjugated with copolymer
nanomicelles through amine functionality of PEG moiety.
On the other hand, fatty acid helps to cross the blood-brain
barrier. So, fatty acid conjugated nanomicelles will have a
good application to improve drug delivery forbrain-related
diseases for a disorder of the central nervous system.[96] The
vascular endothelial growth factor (VGEF) is a major regu-
lating factor for angiogenesis. To load and sustain deliver of
VEGF through a micelle, Kok et al.[97] composed a blend of
two swellable multiblock copolymerssuch as, poly(e-capro-
lactone)-poly(ethylene glycol)-poly(e-caprolactone)-b-poly(L-
lactide) which releases VGEF continuously over 4 weeks in
phosphate-buffered saline pH7.4 at body temperature.
Different kind of architectures like dendrimer, star poly-
mer, mikto-arm star polymer, etc. can be attained by varying
the synthetic procedure and polycaprolactone, poly(ethylene
glycol) segments chain length as well. These polymers may
serve as a better drug delivery vehicle after getting self-
119
assembled in some other ways.[98–102] Buwalda et al.[103]
synthesized an amphiphilic star copolymer for curcumin
drug delivery, consist of PEG-PCL and aromatic functional-
ity benzyl thioether (BTE). This benzyl group makes the
micelle more stable than that of unfunctionalized PEG-PCL
analogue by reducing the CMC and hydrodynamic diameter
along with increasing drug loading capacity. This stability is
probably due to the crosslinking of the core segment via p-p
stacking between the aromatic groups. Aside from the pH-
responsive aggregates, thermo-responsive c-substituted star
block copolymers of polycaprolactone backbone are also
well reported.[104] A glycopolymer conjugated polycaprolac-
tone with porphyrin core star block copolymer, named as
poly(e-caprolactone)-b-poly(gluconamidoethyl methacrylate),
was synthesized by Dai et al.[105] via ROP and atom transfer
radical polymerization (ATRP). This particular polymer is
applicable for photodynamic therapy and targeted delivery
as it releases singlet oxygen under UV radiation along with
specific recognition for Concanavalin A. Galactosylated bio-
degradable copolymer can be well applied for hepatoma tar-
geting DOX where phosphoester moiety involves as
hydrophilic segment instead of poly(ethylene glycol).[106]
Also, lacto bionic acid-modified glycopolymer is a promising
candidate for hepatoma targeted DOX delivery for the treat-
ment of liver cancer.[107]
Double hydrophilic block copolymers (DHBC) have
gained increasing attention as an alternative of amphiphilic
120 P. MANDAL AND R. SHUNMUGAM
Figure 12. Illustration of gold nanorods-cored biodegradable micelles based on (PEG-PCL-LA) block copolymer for NIR-triggered release of doxorubicin in cancer
cells (Reproduced with the permission from ref.[109] Copyright 2013, American Chemical Society).
block copolymers. Here, the copolymer must contain at least
two different water-soluble blocks. One of them is a non-
ionic block which will promote solubilization in water, usu-
ally PEG, and another block is generally a pH-
responsive block.
Nottelet et al.[108] introduced such kind of DHBC com-
posed of PEG moiety with differently functionalized poly-
caprolactone such as hydroxyl-PCL, amino-PCL, or
carboxylic-PCL. The three sets of copolymers are capable of
forming self-aggregates into water and investigation of pH
triggered doxorubicin drug release study and cytotoxicity
with PCL-COOH, shows that this could be further applied
as an interesting drug delivery vehicle for DOX in MCF-7
cancer cells (Figure 11).
We know that near-infrared (NIR) radiation is very
much effective for in vivo imaging and remotely triggered
drug release. It can penetrate the tissues upto 10 cm. It
allows the temporal and spatial control over drug release
very precisely. On the other hand, gold nanorods (AuNR)
are having an efficient NIR induced photothermal effect. To
achieve this goal, Liu et al.[109] have developed a biodegrad-
able lipoylated poly(ethylene glycol)-b-poly(e-caprolactone)
[PEG-PCL-LA] block copolymer with AuNR core (Figure
12). Here, lipoic acid is a naturally occurring biocompatible
compound that is used to develop functional nanoparticle
for intracellular drug and gene delivery. Further, they have
confirmed that the micelle can effectively kill drug-sensitive
and multidrug-resistant cancer cell with NIR triggered
release of doxorubicin drug.
Cheng et al.[110] have synthesized a coumarin anchored
dendrimer for effective gene delivery. Here, the coumarin
moiety in the nanoaggregates cross-linked under UV radi-
ation at 365 nm which further degrades upon irradiation
at 254 nm and consequently releases the cargo molecule.
This dendrimer exhibits the light-triggered codelivery of
5-fluorouracil and a therapeutic gene encoding tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL).
High molecular weight poly(ethylene glycol), preferably
termed as poly(ethylene oxide) is also a hydrophilic seg-
ment, used in the field of drug delivery system.[111] By
altering the chain length and other parameters, it is pos-
sible to generate star-like,[112] comb-like[113] architectural
vehicles for drug loading. Moffitt et al.[114] have reported
a DDS with poly(ethylene oxide) based methoxy substi-
tuted caprolactone copolymer to fine-tune the crystallinity
and a better system was observed than that of unsubsti-
tuted PCL.
There are few reports on graft copolymer-based micelle
formation, maybe due to difficulties and challenges in syn-
thesis. Graft copolymer micelles have several advantages
over block copolymer micelles. They offer low CMC and
consequently enhanced stability, micellar core, and surface
properties which may be governed by the backbone length,
graft density, and graft length. The presence of a sufficient
number of hydrophilic grafts per macromolecules enables
the conjugation. These magnificent characteristics can serve
as high-density targeting ligands for optimal tumor-target-
ing.[115–116] Dong et al.[117] reported poly(e-caprolactone)-
graft-poly(dimethylamino ethylmethacrylate) amphiphilic co-
polymer for gene delivery where the cationic poly(dimethy-
lamino ethylmethacrylate) (PDMAEMA) side-chains were
modified with two electro neutral monomers with different
hydrophobicity:
2-hydroxyethyl methacrylate (HEMA) and 2-hydroxyethyl
acrylate (HEA). Among the polycations, this PDMAEMA
has an outstanding ability to condense DNA stably in aque-
ous solution[118] and the unique mechanism of escape from
lysosomes.[119] These simple modifications with HEA and
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY
Figure 13. Effect of hydrogen peroxide on thioether functionality.
HEMA moieties modify the surface hydrophilicity of the
nanoparticle and significantly affect the gene transfection
efficiency on HeLa cells.
Reactive oxygen species (ROS) is a group of oxygen-con-
taining radicals and non-radical molecules. It plays a key
role in cellular signaling pathways and redox homeosta-
sis.[120] Over expressive ROS results in oxidative stress which
may cause many diseases including cancer. Usually, there
are four types of ROS present such as; hydrogen peroxides
(H2O2), hydroxyl radicals (OH), superoxides (O2), and
peroxynitrites (ONOO). Among these H2O2 is the most
abundant one. So, ROS-responsive materials are needed to
be synthesized to enable site-specific delivery of therapeutics
and imaging agents. Toward this goal polycaprolactone base
copolymers were synthesized including H2O2-responsive
motifs like arylboronic ester,[121] organochalcogens, proline
oligomer crosslinkers,[122] etc. Huang et al.[123] have fabri-
cated an amphiphilic alternating copolymer with thioether
pendant groups through an amine-epoxy click reaction of
3-(methylthio)-propylamine (MSPA) and ethylene glycol
diglycidyl ether. When the micelles were subjected to H2O2,
theses could be disassembled because the hydrophobic thio-
ether groups were transformed to hydrophilic sulfoxide
groups in MSPA units and lost its amphiphilicity
(Figure 13).
The thermo responsive drug carriers undergo significant
phase transition above their lower critical solution tempera-
ture (LCST) which makes deposition of drug molecules and
easy absorption by cells. The phase transition temperatures
can be modified by controlling the molecular weights and
compositions.[124] An ideal LCST of thermo responsive DDS
is greater than the physiological temperature so that the
localized elevated temperature can deform the micelles to
trigger the release of entrapped drug molecules. N-isopropy-
lacrylamide (NIPAM) is a very well-known thermo respon-
sive segment having LCST at 32
C which is less than that
of physiological temperature. To produce a thermo respon-
sive drug delivery vehicle, a triblock copolymer was
synthesized consisting of polycaprolactone, poly(N-isopropy-
lacrylamide), and polycaprolactone, [PCL-b-PNIPAM-b-
PCL]. The experiment showed that the LCST of this copoly-
mer increased to physiological temperature. The drug release
phenomenon then accelerated maybe due to the tempera-
ture-induced structural changes of micelles. The PNIPAM
segment behaves as hydrophobic moiety at elevated tem-
perature which ruptures the miceller morphologies.[125]
Drug delivery devices with two thermo responsive segments
as polyphosphoester and 2-(N,N-dimethylamino)ethyl
121
methacrylate were reported by Wang et al.[126] and Peinado
et al.[127] respectively. Stefan et al.[128] reported thermo
responsive polymeric micelles composed of c-benzyloxy sub-
stituted poly(e-caprolactone) as the hydrophobic block and
c-substituted oligo(ethylene) glycol (OEG) poly(e-caprolac-
tone) as a hydrophilic block with co-loading of DOX and
quercetin drug. They have tuned the LCST by the variation
of the oligo(ethylene) glycol chain length and it observed
that the LCST increased with increasing the chain length.
LCST and drug release behavior is depicted in Figure 14.
The solitary PCL segment is usually less accessible to the
enzymes whereas substituted PCL showed excellent enzyme
driven biodegradation. To accomplish this goal, Jayakannan
et al.[129] have reported random and block copolymers con-
sisted of caprolactone and carboxylic acid substituted capro-
lactone. At first butyl ester conjugated caprolactone was
produced and next carboxylic acid moiety was introduced
by the deprotection of the butyl ester functionality. The top-
ology controlled enzymatic biodegradation was investigated
by varying the carboxylic acid segments. The random
copolymers transformed from semi-crystalline to complete
amorphous nature. On the other hand, block copolymer
retained its semi-crystalline nature upon increasing the butyl
ester group and deprotection as well. As the carboxylic chain
length increased, the block copolymer was sluggish to crys-
tallize. The block copolymer with less number of carboxylic
groups exhibited tight packing and consequently, a slow
drug release phenomenon was observed. But the loosely
packed random copolymer domains provide enhanced
enzymatic biodegradation with burst release of cargo mole-
cules (Figure 15).
Polycaprolactone can also be conjugated with naturally
occurring hydrophilic biopolymers such as chitosan,[130–131]
dextran,[132] cellulose,[133] alginate, etc. for targeting delivery.
Presence of numerous hydroxyl functionalities allows the
chemical modifications for this purpose.
The visibility of cellular processes, internal organs,
tumors, as well as normal tissue can be improved by using
imaging agents. These can be classified as magnetic reson-
ance imaging (MRI) or cellular imaging. Gadolinium is the
most commonly used contrast agent. It shortens T1 and T2
values of tissue water which reflects in positive enhancement
in T1-weighted images and negative enhancement in T2-
weighted images. Pei et al.[134] reported a triblock copolymer
based on poly(glycerol) (PG) and poly(e-caprolactone)
(PCL) for the delivery of tumor-targeted magnetic resonance
agent where gadolinium was chelated with folic acid mole-
cules to the backbone. The super paramagnetic Fe3O4 is
122 P. MANDAL AND R. SHUNMUGAM

Figure 14. Schematic illustration of the preparation and loading of DOX- and Que-loaded micelles and drug release studies. (Reproduced with permission from
ref.[128] Copyright 2020, American Chemical Society).

Figure 15. Programming the enzymatic biodegradation of amphiphilic block and random polycaprolactone copolymer nanocarriers and delivery of anticancer drugs
to cancer cells. (Reproduced with permission from ref.[129] Copyright 2016, American Chemical Society).

another contrast agent which works by decreasing T1 and phenylenevinylene (OPV) for cellular imaging as well as
T2.[135–136] Jayakannan et al.[137] designed a DOX loaded tri- drug delivery application. Thiscopolymer self-assembled in
block copolymer with substituted polycaprolactone and water as spherical nanoparticle with p-core, whereas, in
p-conjugated fluorophore bishydroxyloligo- organic solvents, it produced helical nan fibers. It was
 JOURNAL OF MACROMOLECULAR SCIENCE, PART A: PURE AND APPLIED CHEMISTRY 123

Figure 16. Polymer-cum-p conjugated chromophore triblock copolymer approach for drug delivery and imaging in cancer cells. (Reproduced with permission from
ref.[137] Copyright 2016, American Chemical Society).

susceptible to lysosomal esterase to release the drug mole-

Table 2. PCL based nanoparticles for anticancer drug delivery.
cules and the confocal study confirmed the cell-penetrating
Cancer Polymer Drug
ability of OPV with preferable accumulation in cytoplasm
Lung PVP-PCL Tetrandrine
Lung PCL-PEG-PCL Curcumin
(Figure 16).
Colon Chitosan coated PCL 5-fluorouracil
Colon star-shaped MPEG-PCL Honokiol  Delivery application by electrospun mat formation
Colon PLA-PCL-PGA 5-fluorouracil
Liver star-shaped CA-(PCL-ran-PLA)-b-PEG Docataxel
Liver PCL-SS-PEG-PBA Doxorubicin PCL derived electrospun mats are also well-known drug
Cervical PCL-TPGS Genistein delivery vehicle. These mats have a higher surface area than
Cervical MPEG-PCL-g-PDMAEMA polo-like kinase-1
specific siRNA that of the solvent cast film because of its fibrous nature.
Cervical PCL-PLA-TPGS Docetaxel Due to that reason; a higher amount of drug can be deliv-
Breast MPEG-PCL Cisplatin ered via electrospun mat implantation.[138] Blend and coaxial
Breast PCL-heparin Paclitaxel
Breast MPEG-BPCL Camptothecin are the two types of mechanism for the electro spinning
Ovarian PCL-PAPA-POEGMEA Modified oxoplatin process. The parameters which affect this above-mentioned
Ovarian PEG-PCL Tamoxifen process can be divided into three major categories: solution
Bladder poly-L-lysine-coated PCL Mitomycin C
Leukaemia Poly(alanine-PCL) Imatinib parameter, process parameter and ambient parameter.[139]
Melanoma FA-PEG-PCL Camptothecin Venugopal et al.[140] have fabricated a PCL nanofibre for the
Prostate PSMA-PEG-PCL BL05-HA
Sarcoma PCLLA-PEG-PCLLA 10-hydroxycamptothecin
delivery of an antibiotic drug named as tetracycline hydro-
Esophageal HA-g-PCL Doxorubicin chloride (TC). To fabricate PCL/TC nanofibre, a mixture of
PVP ¼ Poly(vinylpyrrolidone); CA ¼ Cholic acid; PBA ¼ Phenyl boronic acid; solvent [chloroform:methanol (3:1)] was used. PCL exhibited
PLA ¼ Poly(lactic acid); TPGS ¼ a-tocopheryl polyethylene glycol 1000 succin- a transition from hydrophobic to hydrophilic state with time
ate; PDMAEMA ¼ Poly(2-dimethylaminoethyl methacrylate); BPCL ¼ Ester
modified PCL bearing at butyl group; PAPA ¼ Poly(aminopropyl acrylate);
due to TC loading for the controlled release. The delivery
POEGMEA ¼ Poly(polyethene glycol methyl ether acrylate); FA ¼ Folic acid; vehicle for dipyridamole, which is known to induce platelet
PSMA ¼ Prostate-specific membrane aptamer; PCLLA ¼ Poly(caprolactone-co- aggregation inhibition, was prepared by coaxial electro spin-
lactide); HA ¼ Hyaluronic acid.
ning.[141] Furthermore, Alves et al.[142] reported a peptide
124 P. MANDAL AND R. SHUNMUGAM
conjugated PCL nanofibre where the peptide attachment
modifies the average diameters, crystallinity degree and por-
ous size in the polymer network which enhances the mech-
anical strength. The composite was tested for lipophilic
drug, benzocaine resulting in steady release upto 13 h.
Gelatine based core-shell structure of polycaprolactone
(PCL-r-gelatin) bi-component nanofibers were obtained as a
delivery device by coaxial spinning. The reaction was carried
out for 6 h at room temperature using 2,2,2-trifluoroethanol
(TFE) as a solvent.[143] Several other examples of DDS are
also available for cyclodextrin, chitosan, polyurethane, poly(-
ethylene oxide) blend polycaprolactone nanofibre.[144–146]
From the above discussion, we can confirm that amphi-
philic PCL homopolymers or copolymers are mainly used
for targeted delivery of various anticancer drugs. Few anti-
cancer drugs with its PCL-based scaffolds are listed in
Table 2.[147]
(II) Tissue engineering application
Tissue engineering is a strategy by which the therapies
have been revolutionized for the regeneration of various tis-
sues like bone, cartilage, ligament, skeletal muscle, skin, car-
diovascular, nerve tissues and so on. It involves the design
of porous scaffolds with high connectivity and generally
used as a 3 D template to support the attachment and subse-
quent tissue formation. The ideal scaffold should possess
biodegradability, processibility, biocompatibility with con-
trolled degradation kinetics and easy fabrication.[148] The
molecular self-assembly based on polycaprolactone copoly-
mers has shown great potential in the field of soft tissue
engineering like bladder, skin, heart muscle, cornea, nerve
etc. There is an optimum pore size range may be opted as a
function of tissues to be regenerated such as 5-15 mm for
fibroblast in-growth, 20-125 mm for skin regeneration, and
100-300 mm for bladder smooth muscle cell adhesion- and
in-growth, 100-400 mm for bone regeneration.[23] Owing to
this process, it is easy to get fiber diameter on a lower scale
with great control over the 3 D structure.
An example of PCL-PEG-PCL photo cross linked hydro-
gel has been reported for cartilage formation which exhibits
an excellent regeneration in a rabbit model. Here the two
sources of cartilage formation, chondrocytes and bone mar-
row stem cells have been co-cultured with a ratio of 1:4 for
4 weeks.[149] Zhang et al.[150] reported a triblock copolymer
composed of poly(E-caprolactone-co-lactide)-b-poly(ethylene
glycol)-b-poly(E-caprolactone-co-lactide) (PCLA-PEG-
PCLA) which can serve as barriers to prevent the postopera-
tive intestinal adhesion. The aqueous solution of this bio-
degradable copolymer is injectable and it could form
hydrogel due to percolation of self-assembled micelle struc-
ture at body temperature. This hydrogen bonding eventually
starts degrading after 6 weeks. This particular copolymer is
capable of encapsulating cell-adhesive RGD (arginine-gly-
cine-aspartate) peptide to prevent postoperative tissue adhe-
sion.[151] Another example of cartilage tissue formation has
been reported by Honda et al.[152] where L-lactide was used
with polycaprolactone for the synthesis of the copolymer.
This study investigated the chondrocytes grown ability to
generate ectopic cartilage tissue. Considering the versatile
properties like biodegradability, hydrophilicity, swelling and
processibility, it can be concluded that PEG-PCL based
hydrogels could be an appropriate tool to study the interac-
tions between cells or tissues and scaffolds.[153]
3. Conclusion
Polycaprolactone has proved to be the most useful synthetic
polyesters due to its biodegradability, biocompatibility,
mechanical properties and slow degradation rate. It is easy
to synthesis in a cost-effective manner. The physical and
mechanical properties can be altered according to the
requirements through copolymerization. A wide range of
structures can be occurred by the self-assembly processes
which have several applications, especially in the field of
drug delivery and tissue engineering. PCL has the important
certifications like FDA (Food and Drug Administration)
approval and CE (certification) marking which is the most
important thing for commercialization as well as
in vivo studies.
Acknowledgements
P. M. thanks UGC-RGNF SC for her fellowship. R. S. thanks IISER
KOLKATA for infrastructure and funding.
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