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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5985_Библиотеки_им_академика_М_И_Перельмана
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the delivery of proteins, oral uptake of PM, types of polymers utilized in the
administration of micellar drugs, and PM for multiple functionality and protein
delivery.
232 S. Ashique et al.
Keywords
Polymeric micelles · SiRNA · Proteins · Ligands · Nanoparticles · Oral delivery
12.1 Introduction
Although protein medicines offer a lot of potential as targeted therapeutics, their use
is hampered by issues including instability, a brief half-life, and unfavourable
immune reactions. As a result, ways of effectively increasing the availability and
activation of proteins in specific tissues may be found in protein delivery approaches
based on stimuli-responsive nanocarriers. Thus, substantial research is being done
on PM that may encapsulate proteins (Tao et al
. 2020).
The core-shell structure of
PM for developing nanoscale drug delivery device was created via the self-
assembling of amphiphilic block copolymers after dispersion in the aqueous
phase. Amphiphilic di-block-copolymers such as polystyrene and poly(ethylene
glycol) (PEG) and triblock-copolymers (poloxamers) are common and frequently
used polymeric materials for the development of micelles, but graft (like G-chitosan)
and ionic [like PEG-poly(-caprolactone
)-g-polyethyleneimine] copolymers are also
used (Yadav et al.
2019).
As excipients for conventional pharmaceutical
formulations, biocompatible polymers have been widely used in pharmaceutical
research (Bharate et al. 2016; Cabral et al. 2018). More recently, they have been
used in nanomedicines to improve the therapeutic results of strong pharmaceuticals.
The development of micelle-based delivery methods as possible human
nanomedicines has been suggested for several new block copolymers (Lee et al.
2008; Kim et al.
2004).
The delivery of medicinal compounds has been greatly
improved because of several important developments in PM. Due to the functions
the polymer confers on the formulation, standard PM formulations are anticipat ed to
improve the therapeutic efficacy of the medication encapsulated in a protein.
Because PM can release their cargo from the core in a regulated way throughout
systemic circulation, their PK profiles for therapeutic drugs differ from those of
native substan
ces. PM structural characteristics, such as their hydrophilic shell, aid
in preventing opsonization by the complement system and unanticipated drug loss
from serum components, both of which usually lead to the fast clearance of
medicines from systemic circulation (Owens and Peppas
2006).
Due to their many
advantageous properties, such as their capability to access the affected area with
compromised vasculature, longevity, safety, long term drug release, improved
stability (in vivo and in vitro), and capacity to successfully emulsify various poor
soluble drugs, they have become very popular. Additionally, by modifying the
surface of these micelles with different ligands and cell-penetrating moieties, new
activities may be added to enable the tar
geted delivery and intracellular
accumulation of protein-based therapeutics (Jhaveri and Torchilin 2014). PM are the
most effective alternative drug carriers when compared to other micellar systems.
The advantages of mixed PM include the incorporation of noticeably higher medi-
cine doses, longer blood circulation durations, and thermodynamic stability. The PM
core has been designed to have the best durability and drug loading capacity. The
length of hydrophobic blocks and the kind of substituents found in the core have the
biggest effect on PM capacity to carry medicine
s. The insoluble medications can be
contained in the micellar core via either chemical conjugation or physical trapping.
12 Polymeric Micelles in the Delivery of Proteins 233
12.2 Polymeric Micelles (PM) as Therapeutic Carriers for Protein
Delivery
The use of proteins and peptides as PM targeting ligands is also quite common. The
creation of transferrin-targeted nanocarriers is made possible by the transferrin
receptor (TfR), which is overexpressed in many malignancies (Singh
1999). Trans-
ferrin (Tf), an endogenous ligand for PM, or antibodies against TfR may be used to
modify them (Torchilin 2006). Sawant et al. developed micelle of transferrin
modified PEG-PE (polyethylene glycol-phosphatidylethanolamine) to deliver a
CDK inhibitor “R457.” The drug targeting efficacy and cell toxi city were evaluated
in vitro and in vivo using A2780 ovarian cancer cell lines (ovarian carcinomas).
Antitumour activity was improved as compared to free drug (Sawant et al.
2013).
Water is distributed in PM in an anisotropic manner, with the amount of water
decreasing as it moves from the surface to the hydrophobic centre. Thus, the polarity
of the medication determines where it will be located within micelles: hydrophobic
APIs (active pharmaceutical ingredients) will locate within core (lipophilic) or on the
surface depending upon drug polarity and hydrophilicity. Generally, hydrophilic
candidates are lodged within centre or surface of the micellar structure, whereas
lipophilic drug candidate settled within lipophilic core of micelle (Rangel-Yagui
et al.
2005). Most of the time, unimers and polyion complex micelles are used to
chemically conjugate hydrophilic molecules, or they use electrostatic interactions to
load hydrophilic molecules. For instance, RNA is often loaded into amphiphilic
block copolymers by the insertion of polycations and then employed for RNA
condensation. Amphiphile micellar solutions are an efficient method of delivering
medications to their targets. Water-insoluble medicines are easily soluble in the
hydrophobic environment of the micelle core and loaded for distribution to the
necessary sites. Targeted protein drug delivery systems are created to ensure mini-
mal drug loss and degradation, avoid negative side effects, boost the bioavailability
of protein pharmaceuticals, and raise the concentration of medications in the desired
zone of interest. Insoluble polymers (synesthetic and natural), soluble polymers,
liposomes, micelles, microparticles, cell ghosts, cells, and amphiphilic polymers are
just a few of the numerous drug carriers that are often used (Yokoyama
1998).
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234 S. Ashique et al.
12.3 Advantages and Challenges of Polymeric Micelles
(PM) for the Delivery of Proteins
Due to the potential of PM to boost the solubility and stability of aquaphobic
medications and their in vivo therapeutic efficacy, which is equivalent to or better
than that of the free drug, PM have received scientific attention in recent years. PM
may be made to be big enough to prevent early clearance owing to fast glomerular
filtration, which prolongs circulation time, by regulating their size. The particle size
is kept tiny enough to safely pass through the smallest veins at the same time. The
properties of the PM can improve the cellular localization of the drug loaded
micelles and provide a different pathway for endosomal internalization. Because
the drug delivery is selective and targeted to tissues, these properties aid PM in
having a better mean residence time (MRT), which may lead to a lowered dose,
higher bioavailability, as well as a potential reduction in the risk of nonspecific organ
toxicity. To improve medication delivery to particular sites and penetrate tumours
more effectively, PM have been found to have a higher therapeutic index. Thus, PM
may be useful for enhancing biodistribution while posing little threat of accumula-
tion and persistent toxicity in the body. While research on PM has advanced
significantly as excellent nanocarriers for pharmaceuticals, particularly hydrophilic
medications, their development has been hampered by issues with poor stability and
limited drug loading. Nevertheless, due to the chemical adaptability provided by
amphiphilic block copolymers, PM may be designed to circumvent these difficulties.
Modifying the micellar core is one method for raising the drug loading capacity and
micellar stability, and it has been studied in several studies as one method for
improving the loading efficiency of PM. Wan et al. loaded paclitaxel and cisplatin
into micelles made of amphiphilic copolymers for the purpose of targeting ovarian
and breast cancers, resulting in a noticeably higher loading efficiency (Wan et al.
2019)
. I
n addition to the numerous uses for PM, there are several difficulties that
need to be overcome before they may be considered as viable drug carriers. These
include enhancing drug loading effectiveness even further, stabilizing blood aerosol
injection, and facilitating transport across cell membranes.
They physi
cally entrap sparingly soluble medications, improve their bioavailabil-
ity, and transport them to the intended site of action at concentrations that are greater
than its intrinsic water solubility. The addition of micelles also improves the drug’s
stability. Additionally, compared to free pharmaceuticals , there are less negative side
effects due to reduced interaction of the medication with inactivating species, such as
enzymes found in bodily fluids (
Torchilin 2001). Micellar delivery systems’ tiny size
(10–30 nm) and narrow size distribution are by far their most distinctive
characteristics, setting them apart from other particulate drug carri ers (Florence
and Hussain 2001). Nonionic surfactant-based micelles are often employed as
drug carrier for controlled drug delivery (Bardelmeijer et al. 2002). Since most
organizations established their individual micelle system made from distinct
hydrophilic-lipophilic combinations because of the high degree of activity, this
field now has a significant lot of diversity. Figure
12.1 depicts
the schematic
representation of PM.
12 Polymeric Micelles in the Delivery of Proteins 235
Fig. 12.1 Schematic representation of advantage of micelles
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236 S. Ashique et al.
12.4 Oral Uptake of Polymeric Micelles (PM)
PM have been tested for oral administration for a variety of therapeutic goals,
including increasing apparent drug solubility in GI fluids and facilitating absorption,
penetrating pathological GI tract regions for locoregional treatment, carrying the
drug directly to the bloodstream, minimizing pre-systemic losses, and targeting the
drug to precise tissues or cells in the body after oral absorption. PM have been tested
for oral administration for a variety of therapeutic goals, including increasing
apparent drug solubility in GI fluids and facilitating absorption, penetrating patho-
logical GI tract regions for locoregional treatment, carrying the drug directly to the
bloodstream, minimizing pre-systemic losses, and targeting the drug to specific
tissue or ce lls in the body after oral absorption (Simões et al. 2015).
12.5 Types of Polymers Utilized in the Administration
of Micellar Drugs
Graft copolymers, amphiphilic block copolymers, and triblock copolymers are
frequently used to create PM. According to its compatibility with the integrated
medication, stability, drug release profile, and toxicity, the block polymer of the
hydrophobic core is selected. One can modify the medication release from these
block copolymers. Micelles can also be further altered by having the shell cross-
linked, having the PM surfaces functionalized, and linking ligand
s (aptamers and
antibodies) to the surface for active targeting. Multigraft copolymers are generally
comprised of minimum three homopolymers joined by a common branch. A graft
polymer possessed multiple polymer chain acting as both the side grafted polymer
and the backbone of the polymer. They gain from the transplant as well as the
advantages of the backbone (Kulthe et al.
2012).
A hyperbranched polymer with a
significant number of functional end group belongs to another class of polymers.
Because they have so many end groups, they may readily have their characteristics
changed, making them an ideal choice for drug release under certain responsive
stimuli such as pH, electrolytic strength, and temperature. Several varieties of
manufactured polyester amide and poly(urea-urethane) hyperbranched amphiphilic
polymers can be developed and a
ltered to be utilized as a carrier for hydrophobic
medicines, such as anticancer therapy (Gao and Yan
2
004). Since each polymer has
a special benefit, choosing the right polymer is crucial for extending the circu lation
period and ensuring a regulated release of the medicine. Since they have all been
given FDA approval for biomedical uses in humans, polymers including PLGA
[poly(lactic-co-glycolic acid], PCL [poly(-caprolactone)], and PLA [poly(lactic
acid)] are frequently utilized to form the lipophilic core (Cagel et al. 2017). Fig-
ure 12.2 describes the drug loaded PM with several targeting functions.
12 Polymeric Micelles in the Delivery of Proteins 237
Fig. 12.2 Drug loaded polymeric micelles with several targeting functions
12.6 Stimuli Sensitive Micelles for Delivery of Protein
When exposed to high temperatures, thermo-responsive PM alter structurally; this
characteristic may be used to direct the deposition of protein drugs precisely where it
is desired. Now, scientists utilized the concept of thermoresponsive polymer for the
drug release. Therefore, a drug can be allowed to release loaded payload due to
temperature triggered transition in the thermosensitive polymer based micelle above
or below critical solution temperature (CST) (Rijcken et al.
2007). Above the LCST
(low CST), these thermosensitive polymers solubilize, releasing the medication from
the carrier. Therefore, in this form of micellar system, LCST is the most important
factor. Another external stimulus that has been employed to cause the release of
drugs from stimuli-sensitive multifunctional PM is a magnetic field. A thermo-
sensitive star-block copolymer was used in one study to create magnetothermally
responsive drug loaded micelles by fusing the concepts of temperature-triggered
drug release with the application of a magnetic field (Ji et al.
2014). An external
magnetic stimulation was used to locate the micelles, and after that, the temperature
rose, causing the thermoresponsive micelles to release the medication. To obtain
desired release of payloads, PM may be designed to react to a variety of stimuli
(intrinsic or extrinsic) of various sources (chemical, physical, and biological sources)
(Cheng et al.
2013). The therapeutic payloads of PM that are “environmentally
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sensitive” or “smart” can be released by altering their structural composition in
response to the stimuli. As a result of the reaction, micelles may degrade or become
unstable, isomerize, polymerize, or aggregate supramolecular (Fleige et al. 2012)
(Table 12.1). Figure 12.3 depicts the multifunctional PM for oral delivery of drugs.
238 S. Ashique et al.
12.7 Polymeric Micelles (PM) for Multiple Functionality
and Protein Delivery
At present, multifunctional PM have been the focus of substantial research for
localized delivery drug and nucleic acid such as RNA. Over the past several years,
various amphiphilic block copolymers were synthesized and developed for delivery
of siRNA in micellar construct. These fundamental building blocks are regularly
enhanced to get the most out of them by adding certain ligands or ethically sound
building blocks or linkages. A fundamental goal of all siRNA delivery systems,
including micelles, is to stop siRNA from degrading from the point at which it enters
the bloods tream to the point at which it travels via the endocytic route for intracellu-
lar trafficking and escapes the endosome. In their paper, several authors utilized
multifunctional micelles for delivery either drug or nucleic acid, or co-administration
of drug and NA by allowing self-assembling of RNA with block copolymer
(s) (Christie et al. 2012) (Table 12.2). Figure 12.4 shows the schematic representa-
tion of the phenomena regulating in vivo drug delivery, in terms of both rate and
location, from PM.
12.8 Co-delivery of Drugs and siRNA Using Multifunctional
Micelles
The siRNA therapy based on PM has shown remarkable promise and is presently the
focus of intensive study. However, it is extremely possible that tumours will have
genetic changes, which might lower the usefulness of siRNA as a solitary agent in
the therapy of malignancies (Liu et al. 2013
). Traditional anticancer medications also
have issue s with off-target effect and MDR which is mainly responsible for substan-
tial impairment in cancer treatment. Due to the nonspecific character of these
inhibitors, there has been relatively little clinical success in the creation of
compounds that block the action of drug transporter proteins like P-glycoprotein
(Pg-p), which is produced by the MDR1-gene, to sensitize tumour cells to anticancer
drugs (Shukla et a
l. 2008). In these circumstances, it would be more advantageous to
treat cancer using RNAi to directly reduce Pg-p expression rather than only its
function by suppressing the expression of MDR genes after conventional chemo-
therapy (Wu et al. 2003). Studies show that pre-treating cancer cells with siRNAs
prior to treating them with conventional anticancer medications can greatly increase
the cells’ sensitivity to the drug and increase the effectiveness of therapy (Spankuch
et al.
2007; Macdiarmid et al. 2009). To have the greatest effect in vivo, however,
siRNA and medicine must be given to the same tumour cell at the same time
(continued)
12 Polymeric Micelles in the Delivery of Proteins 239
Table 12.1 Mechanistic perspective of some polymeric micelles (PM) for drug release in vitro under specific responsive stimuli
Drug loaded micelles Mechanism of drug release References
DOX loaded chondroitin sulfate-histamine based micelle pH (acidic) triggered release of DIX from micelle due to changed
conjugate of histamine residue by protonation
Yu et al. (2013)
Camptothecin and Nile red based poly(ketal adipate)-co-PEG
(PKA-PEG) micelle
The polymeric co-block of ketal linkage is cleaved from the
backbone of polymer under acidic condition and resulting in the
drug release
Lee et al. (2013)
siRNA loaded mPEG–PCL–CH2R4H2C (cell-penetrating peptide)
micelle. C, H, and R represent cysteine, histidine, and arginine
siRNA responsible to express VEGR is loaded in the micelle.
Cysteine is a sulfide amino acid. Therefore, cleavage of S-S linkage
in the cytoplasm results in the drug release (GSH, redox)
Tanaka et al.
(2013)
siRNA loaded siRNA-SS-PLGA)/linear PEI (polyethyleneimine) GSH (redox)
Reduction of S-S bond (disulfide bond breaking) causes GFP
siRNA release in the cytoplasm
Lee et al. (2011)
Gemcitabine loaded PEG-b-poly(2-methyl-2-carboxylpropylene
carbonate)-g-gemcitabine-g-dodecanol (PEG-b-PCC-g-GC-g-DC)
micelle
Cathepsin-B (an enzyme) based hydrolysis of amide bond to
disintegrate micelles and subsequent release of the drug
Chitkara et al.
(2013)
Cisplatin and paclitaxel loaded PEG-b-poly(
L-glutamic acid)-b-
poly(
L-phenylalanine) (PEG-b-PGlu-b-PPhe) micelle
Polypeptide bond is sensitive to cathepsin-B enzyme. Micelles
containing polypeptide bond in building block of polymer were
cleaved by the same enzyme at low pH (protected in lysozyme)
Desale et al.
(2013)
DOX loaded pluronic F105 (PEO-PPO-PEO) based micelle Ultrasound creates a cavitation and the generated transient
cavitation by applying impulse of 70 kHz disrupts micelles and
subsequent release of DOX
Husseini et al.
(
2013)
siRNA loaded nanobubbles (NB) through hetero-assembling of
mPEG-b-P(
L-lysine). Micelles of siRNA and gas loaded in
liposomes to tailor siRNA nanobubbles (NB)
Ultrasound creates a cavitation and the generated transient
cavitation by applying impulse of low frequency (kHz) NB and
subsequent release of siRNA (sonoporation effect)
Yin et al. (2013)
DOX probed folic acid/dextran-retinoic acid magnetic
nanoparticles.
Localized internalization of micelle responsive to an external
magnetic field (0.42 T). Magnetic effect produced by magnetic NPs
Varshosaz et al.
(
2013)
DOX loaded PEG-b-PCL and SPION SPION generates hyperthermia due to heating and subsequent
release of DOX from micelle
Glover et al.
(
2013)
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Table 12.1 (continued)
Drug loaded micelles Mechanism of drug release References
DOX
l
oaded
P-(NIPAAm-co-NHMAAm)-b-PCL
micelles The
backbone
of
poly-(NIPAAm-co-HMAAm)
shell
undergoes
from
hydrophilic
to
hydrophobic
transition and release of DOX
above the lowest critical solution temperature (LCST) of 38 °C,
after collapsing micelle structure
Wang et al.
(2014)
Two graft biocompatible copolymers such as chitosan-g-poly
(N-isopropylacrylamide) (CS-g-PNIPAM) and carboxymethyl
cellulose-g-poly(N-isopropylacrylamide) (CMC-g-PNIPAM)
Thermoresponsive polyelectrolyte complex micelle loaded
5-fluorouracil (5-FU) for controlled release of 5-FU above LCST
(37 °C)
Core was formed of positively charged chitosan and negatively
charged CMC by electrolyte interaction
Hydrogen bonding between 5-FU and micelle increased the drug
loading
Micelles were deformed under the changed electrolytic ionic
strength, pH, and temperature
Li et al. (2013a)
Rifampicin and paclitaxel loaded PEO-b-P(LGA-co-COU) based
micelle
Photoresponsive drug release mechanism. Near infrared radiation
caused shift in hydrophilic-hydrophobic balance due to the light
absorption by the coumarin moiety which caused instability of
micellar structure and subsequent release of the drugs
Kumar et al.
(2012)
Curcumin loaded dialkyl cyano stilbene polymethacrylate-b-PEO
(PDACS-b-PEO) micelle
Under UV light, stilbene exhibits trans-cis photo-isomerization
transition which results in low polymeric hydrophobicity and
cleaves micelles to release loaded curcumin
Menon et al.
(2011)
240 S. Ashique et al.
following systemic distribution. For the best potential collaboration, they ought to
also be distributed optimally among cells (Sun et al.
2011). In this chapter, we
examine many examples of such PM, which include siRNA and medications inside
of a single nanocarrier. Multifunctional PEO-b-PCL block copolymer micelles
having functional modifications on both blocks. These micelles may carry out a
number of functions, including pH-triggered drug release in endosomes, siRNA and
DOX co-delivery, facilitated cell membrane translocation, passive and active
targeting, and siRNA and DOX administration. These mi
celles may carry out a
range of functions, such as pH-triggered drug release in endosomes, siRNA and
DOX co-delivery, simpler cell membrane translocation, passive and active targeting,
and siRNA and DOX administration. Using a pH-sensitive hydrazone linkage, the
PCL core of the micelles may conjugate short polyamines [spermine (SP)] to
chemically combine MDR1 siRNA and DOX, as well as fluorescent imaging probes
to monitor micelles in vitro and in vivo. Two ligands were
added to the virus-like
shell of these micelles: a cell-penetrating TAT-peptide to aid in intracellular absorp-
tion and an active targeting ligand, RGD4C specific for integrin (ɑvβ3) receptors
(Table
12.3).
12 Polymeric Micelles in the Delivery of Proteins 241
Fig. 12.3 Multifunctional polymeric micelle
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