Self-Assembled Amphiphilic Copolymers in Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 25948

Special Issue Editors

Department of Exact Sciences, “Ion Ionescu de la Brad” Iasi University of Life Sciences, 700490 Iasi, Romania
Interests: self-assembled materials; drug delivery systems; controlled release; biomaterials; polymers; liposomes; nanoparticles nanocomposites; nanomaterials synthesis and characterization;
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Guest Editor
Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, 700487 Iasi, Romania
Interests: hybrid nanomaterials; G-quartet hydrogels; nanomaterials synthesis and characterization; Atomic Force Microscopy; Raman and SERS
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to publish your valuable research results in this Special Issue titled “Application of Self-Assembled Amphiphilic Copolymers in Drug Delivery”. Amphiphilic copolymers present a unique chemical structure that includes both hydrophilic and hydrophobic chains, which trigger a self-assembling behavior in selective solvents due to the hydrophilic/hydrophobic interactions among different polymer blocks. Based on this behavior, amphiphilic copolymers can form micelles or polymer vesicles (polymersomes), making them attractive for numerous applications in biomedicine, including their usage as drug delivery systems. There is a high demand for new drug-polymer formulations to be used as effective carriers that allow for an efficient controlled release of the active substance in the targeted area. From this point of view, amphiphilic copolymers are emerging in biomedicine, where there is a stringent need for a system responsive to external stimuli (pH, temperature, solvents, etc.) and that is capable of loading and releasing the incorporated drug.

This Special Issue aims to collect papers related to all aspects regarding the development (process engineering, synthesis, characterization, theoretical modelling, etc.) of self-assembled amphiphilic copolymers and their application as new drug delivery systems. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Synthesis routes and property control;
  • Fine tuning of amphiphilic copolymers’ properties;
  • Chemical modifications of amphiphilic copolymers;
  • Process engineering of polymer matrices;
  • Encapsulation and delivery of hydrophilic drugs from hydrophobic copolymers;
  • Encapsulation and delivery of hydrophobic drugs from hydrophilic copolymers;
  • Controlled drug delivery studies;
  • Drug targeting.

We look forward to receiving your contributions.

Dr. Ana Cazacu
Dr. Elena-Laura Ursu
Guest Editors

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Keywords

  • self-assembly
  • amphiphilic block copolymers
  • nanostructures
  • drug delivery systems
  • targeted drug delivery
  • controlled release
  • kinetics studies
  • carriers
  • micelles
  • polymersomes

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Published Papers (14 papers)

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23 pages, 4805 KiB  
Article
Development, Characterization and Pharmacological Evaluation of Cannabidiol-Loaded Long Circulating Niosomes
by Viliana Gugleva, Katerina Ahchiyska, Dilyana Georgieva, Rositsa Mihaylova, Spiro Konstantinov, Erik Dimitrov, Natalia Toncheva-Moncheva, Stanislav Rangelov, Aleksander Forys, Barbara Trzebicka and Denitsa Momekova
Pharmaceutics 2023, 15(10), 2414; https://doi.org/10.3390/pharmaceutics15102414 - 3 Oct 2023
Cited by 1 | Viewed by 1333
Abstract
Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming [...] Read more.
Cannabidiol (CBD) is a promising drug candidate with pleiotropic pharmacological activity, whose low aqueous solubility and unfavorable pharmacokinetics have presented obstacles to its full clinical implementation. The rational design of nanocarriers, including niosomes for CBD encapsulation, can provide a plausible approach to overcoming these limitations. The present study is focused on exploring the feasibility of copolymer-modified niosomes as platforms for systemic delivery of CBD. To confer steric stabilization, the niosomal membranes were grafted with newly synthesized amphiphilic linear or star-shaped 3- and 4-arm star-shaped copolymers based on polyglycidol (PG) and poly(ε-caprolactone) (PCL) blocks. The niosomes were prepared by film hydration method and were characterized by DLS, cryo-TEM, encapsulation efficacy, and in vitro release. Free and formulated cannabidiol were further investigated for cytotoxicity and pro-apoptotic and anti-inflammatory activities in vitro in three human tumor cell lines. The optimal formulation, based on Tween 60:Span60:Chol (3.5:3.5:3 molar ration) modified with 2.5 mol% star-shaped 3-arm copolymer, is characterized by a size of 235 nm, high encapsulation of CBD (94%), and controlled release properties. Niosomal cannabidiol retained the antineoplastic activity of the free agent, but noteworthy superior apoptogenic and inflammatory biomarker-modulating effects were established at equieffective exposure vs. the free drug. Specific alterations in key signaling molecules, implicated in programmed cell death, cancer cell biology, and inflammation, were recorded with the niosomal formulations. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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12 pages, 3226 KiB  
Article
Inherently Fluorescent Peanut-Shaped Polymersomes for Active Cargo Transportation
by Jianhong Wang, Yingtong Luo, Hanglong Wu, Shoupeng Cao, Loai K. E. A. Abdelmohsen, Jingxin Shao and Jan C. M. van Hest
Pharmaceutics 2023, 15(7), 1986; https://doi.org/10.3390/pharmaceutics15071986 - 20 Jul 2023
Cited by 2 | Viewed by 1373
Abstract
Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and [...] Read more.
Nanomotors have been extensively explored for various applications in nanomedicine, especially in cargo transportation. Motile properties enable them to deliver pharmaceutical ingredients more efficiently to the targeted site. However, it still remains a challenge to design motor systems that are therapeutically active and can also be effectively traced when taken up by cells. Here, we designed a nanomotor with integrated fluorescence and therapeutic potential based on biodegradable polymersomes equipped with aggregation-induced emission (AIE) agents. The AIE segments provided the polymersomes with autofluorescence, facilitating the visualization of cell uptake. Furthermore, the membrane structure enabled the reshaping of the AIE polymersomes into asymmetric, peanut-shaped polymersomes. Upon laser irradiation, these peanut polymersomes not only displayed fluorescence, but also produced reactive oxygen species (ROS). Because of their specific shape, the ROS gradient induced motility in these particles. As ROS is also used for cancer cell treatment, the peanut polymersomes not only acted as delivery vehicles but also as therapeutic agents. As an integrated platform, these peanut polymersomes therefore represent an interesting delivery system with biomedical potential. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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19 pages, 4392 KiB  
Article
The Nanostructured Self-Assembly and Thermoresponsiveness in Water of Amphiphilic Copolymers Carrying Oligoethylene Glycol and Polysiloxane Side Chains
by Elisa Guazzelli, Giuseppe Pisano, Marco Turriani, Tarita Biver, Manfred Kriechbaum, Frank Uhlig, Giancarlo Galli and Elisa Martinelli
Pharmaceutics 2023, 15(6), 1703; https://doi.org/10.3390/pharmaceutics15061703 - 10 Jun 2023
Viewed by 1027
Abstract
Amphiphilic copolymer self-assembly is a straightforward approach to obtain responsive micelles, nanoparticles, and vesicles that are particularly attractive for biomedicine, i.e., for the delivery of functional molecules. Here, amphiphilic copolymers of hydrophobic polysiloxane methacrylate and hydrophilic oligo (ethylene glycol) methyl ether methacrylate with [...] Read more.
Amphiphilic copolymer self-assembly is a straightforward approach to obtain responsive micelles, nanoparticles, and vesicles that are particularly attractive for biomedicine, i.e., for the delivery of functional molecules. Here, amphiphilic copolymers of hydrophobic polysiloxane methacrylate and hydrophilic oligo (ethylene glycol) methyl ether methacrylate with different lengths of oxyethylenic side chains were synthesized via controlled RAFT radical polymerization and characterized both thermally and in solution. In particular, the thermoresponsive and self-assembling behavior of the water-soluble copolymers in water was investigated via complementary techniques such as light transmittance, dynamic light scattering (DLS), and small-angle X-ray scattering (SAXS) measurements. All the copolymers synthesized were thermoresponsive, displaying a cloud point temperature (Tcp) strongly dependent on macromolecular parameters such as the length of the oligo(ethylene glycol) side chains and the content of the SiMA counits, as well as the concentration of the copolymer in water, which is consistent with a lower critical solution temperature (LCST)-type behavior. SAXS analysis revealed that the copolymers formed nanostructures in water below Tcp, whose dimension and shape depended on the content of the hydrophobic components in the copolymer. The hydrodynamic diameter (Dh) determined by DLS increased with the amount of SiMA and the associated morphology at higher SiMA contents was found to be pearl-necklace-micelle-like, composed of connected hydrophobic cores. These novel amphiphilic copolymers were able to modulate thermoresponsiveness in water in a wide range of temperatures, including the physiological temperature, as well as the dimension and shape of their nanostructured assemblies, simply by varying their chemical composition and the length of the hydrophilic side chains. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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14 pages, 3858 KiB  
Article
Hydrophobic Modification of Poly(γ-glutamic acid) by Grafting 4-Phenyl-butyl Side Groups for the Encapsulation and Release of Doxorubicin
by Porochista Dorost, Montserrat García-Alvarez and Antxon Martínez de Ilarduya
Pharmaceutics 2023, 15(5), 1377; https://doi.org/10.3390/pharmaceutics15051377 - 29 Apr 2023
Viewed by 1423
Abstract
The delivery of drugs is a great challenge, since most of active pharmaceutical ingredients developed today are hydrophobic and poorly water soluble. From this perspective, drug encapsulation on biodegradable and biocompatible polymers can surpass this problem. Poly(γ-glutamic acid) (PGGA), a bioedible and biocompatible [...] Read more.
The delivery of drugs is a great challenge, since most of active pharmaceutical ingredients developed today are hydrophobic and poorly water soluble. From this perspective, drug encapsulation on biodegradable and biocompatible polymers can surpass this problem. Poly(γ-glutamic acid) (PGGA), a bioedible and biocompatible polymer has been chosen for this purpose. Carboxylic side groups of PGGA have been partially esterified with 4-phenyl-butyl bromide, producing a series of aliphatic–aromatic ester derivatives with different hydrophilic–lipophilic balances. Using nanoprecipitation or emulsion/evaporation methods, these copolymers were self-assembled in a water solution, forming nanoparticles with average diameters between 89 and 374 nm and zeta potential values between −13.1 and −49.5 mV. The hydrophobic core containing 4-phenyl-butyl side groups was used for the encapsulation of an anticancer drug, such as Doxorubicin (DOX). The highest encapsulation efficiency was reached for a copolymer derived from PGGA, with a 46 mol% degree of esterification. Drug release studies carried out for 5 days at different pHs (4.2 and 7.4) indicated that DOX was released faster at pH 4.2, revealing the potential of these nanoparticles as chemotherapy agents. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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29 pages, 6477 KiB  
Article
Amphiphilic Polypeptides Obtained by Post-Polymerization Modification of Poly-l-Lysine as Systems for Combined Delivery of Paclitaxel and siRNA
by Apollinariia Dzhuzha, Erik Gandalipov, Viktor Korzhikov-Vlakh, Elena Katernyuk, Natalia Zakharova, Sergey Silonov, Tatiana Tennikova and Evgenia Korzhikova-Vlakh
Pharmaceutics 2023, 15(4), 1308; https://doi.org/10.3390/pharmaceutics15041308 - 21 Apr 2023
Cited by 3 | Viewed by 1607
Abstract
The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both [...] Read more.
The development of effective anti-cancer therapeutics remains one of the current pharmaceutical challenges. The joint delivery of chemotherapeutic agents and biopharmaceuticals is a cutting-edge approach to creating therapeutic agents of enhanced efficacy. In this study, amphiphilic polypeptide delivery systems capable of loading both hydrophobic drug and small interfering RNA (siRNA) were developed. The synthesis of amphiphilic polypeptides included two steps: (i) synthesis of poly-αl-lysine by ring-opening polymerization and (ii) its post-polymerization modification with hydrophobic l-amino acid and l-arginine/l-histidine. The obtained polymers were used for the preparation of single and dual delivery systems of PTX and short double-stranded nucleic acid. The obtained double component systems were quite compact and had a hydrodynamic diameter in the range of 90–200 nm depending on the polypeptide. The release of PTX from the formulations was studied, and the release profiles were approximated using a number of mathematical dissolution models to establish the most probable release mechanism. A determination of the cytotoxicity in normal (HEK 293T) and cancer (HeLa and A549) cells revealed the higher toxicity of the polypeptide particles to cancer cells. The separate evaluation of the biological activity of PTX and anti-GFP siRNA formulations testified the inhibitory efficiency of PTX formulations based on all polypeptides (IC50 4.5–6.2 ng/mL), while gene silencing was effective only for the Tyr-Arg-containing polypeptide (56–70% GFP knockdown). Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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19 pages, 9026 KiB  
Article
Hyperbranched Copolymers of Methacrylic Acid and Lauryl Methacrylate H-P(MAA-co-LMA): Synthetic Aspects and Interactions with Biorelevant Compounds
by Anastasia Balafouti and Stergios Pispas
Pharmaceutics 2023, 15(4), 1198; https://doi.org/10.3390/pharmaceutics15041198 - 9 Apr 2023
Cited by 4 | Viewed by 1853
Abstract
The synthesis of novel copolymers using one-step reversible addition-fragmentation chain transfer (RAFT) copolymerization of biocompatible methacrylic acid (MAA), lauryl methacrylate (LMA), and difunctional ethylene glycol dimethacrylate (EGDMA) as a branching agent is reported. The obtained amphiphilic hyperbranched H-P(MAA-co-LMA) copolymers are molecularly characterized by [...] Read more.
The synthesis of novel copolymers using one-step reversible addition-fragmentation chain transfer (RAFT) copolymerization of biocompatible methacrylic acid (MAA), lauryl methacrylate (LMA), and difunctional ethylene glycol dimethacrylate (EGDMA) as a branching agent is reported. The obtained amphiphilic hyperbranched H-P(MAA-co-LMA) copolymers are molecularly characterized by size exclusion chromatography (SEC), FTIR, and 1H-NMR spectroscopy, and subsequently investigated in terms of their self-assembly behavior in aqueous media. The formation of nanoaggregates of varying size, mass, and homogeneity, depending on the copolymer composition and solution conditions such as concentration or pH variation, is demonstrated by light scattering and spectroscopic techniques. Furthermore, drug encapsulation properties are studied by incorporating the low bioavailability drug, curcumin, in the nano-aggregate hydrophobic domains, which can also act as a bioimaging agent. The interaction of polyelectrolyte MAA units with model proteins is described to examine protein complexation capacity relevant to enzyme immobilization strategies, as well as explore copolymer self-assembly in simulated physiological media. The results confirm that these copolymer nanosystems could provide competent biocarriers for imaging and drug or protein delivery/enzyme immobilization applications. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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20 pages, 3738 KiB  
Article
Smart Poly(lactide)-b-poly(triethylene glycol methyl ether methacrylate) (PLA-b-PTEGMA) Block Copolymers: One-Pot Synthesis, Temperature Behavior, and Controlled Release of Paclitaxel
by Svetlana Lukáš Petrova, Martina Vragović, Ewa Pavlova, Zulfiya Černochová, Alessandro Jäger, Eliézer Jäger and Rafał Konefał
Pharmaceutics 2023, 15(4), 1191; https://doi.org/10.3390/pharmaceutics15041191 - 8 Apr 2023
Cited by 2 | Viewed by 2049
Abstract
This paper introduces a new class of amphiphilic block copolymers created by combining two polymers: polylactic acid (PLA), a biocompatible and biodegradable hydrophobic polyester used for cargo encapsulation, and a hydrophilic polymer composed of oligo ethylene glycol chains (triethylene glycol methyl ether methacrylate, [...] Read more.
This paper introduces a new class of amphiphilic block copolymers created by combining two polymers: polylactic acid (PLA), a biocompatible and biodegradable hydrophobic polyester used for cargo encapsulation, and a hydrophilic polymer composed of oligo ethylene glycol chains (triethylene glycol methyl ether methacrylate, TEGMA), which provides stability and repellent properties with added thermo-responsiveness. The PLA-b-PTEGMA block copolymers were synthesized using ring-opening polymerization (ROP) and reversible addition–fragmentation chain transfer (RAFT) polymerization (ROP-RAFT), resulting in varying ratios between the hydrophobic and hydrophilic blocks. Standard techniques, such as size exclusion chromatography (SEC) and 1H NMR spectroscopy, were used to characterize the block copolymers, while 1H NMR spectroscopy, 2D nuclear Overhauser effect spectroscopy (NOESY), and dynamic light scattering (DLS) were used to analyze the effect of the hydrophobic PLA block on the LCST of the PTEGMA block in aqueous solutions. The results show that the LCST values for the block copolymers decreased with increasing PLA content in the copolymer. The selected block copolymer presented LCST transitions at physiologically relevant temperatures, making it suitable for manufacturing nanoparticles (NPs) and drug encapsulation-release of the chemotherapeutic paclitaxel (PTX) via temperature-triggered drug release mechanism. The drug release profile was found to be temperature-dependent, with PTX release being sustained at all tested conditions, but substantially accelerated at 37 and 40 °C compared to 25 °C. The NPs were stable under simulated physiological conditions. These findings demonstrate that the addition of hydrophobic monomers, such as PLA, can tune the LCST temperatures of thermo-responsive polymers, and that PLA-b-PTEGMA copolymers have great potential for use in drug and gene delivery systems via temperature-triggered drug release mechanisms in biomedicine applications. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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18 pages, 4410 KiB  
Article
Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application
by Sonyabapu Yadav, Kalyan Ramesh, Obireddy Sreekanth Reddy, Viswanathan Karthika, Parveen Kumar, Sung-Han Jo, Seong II Yoo, Sang-Hyug Park and Kwon Taek Lim
Pharmaceutics 2023, 15(4), 1159; https://doi.org/10.3390/pharmaceutics15041159 - 6 Apr 2023
Cited by 7 | Viewed by 1695
Abstract
In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique [...] Read more.
In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)2k-b-poly(furfuryl methacrylate)1.5k (PEO2k-b-PFMA1.5k), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO2k-b-PFMA1.5k from FMA monomers and PEO2k-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H2O2, while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO2k-b-PFMA1.5k-Se)2 micelles varied more significantly in response to changes in the redox environment than (PEO2k-b-PFMA1.5k-S)2 micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO2k-b-PFMA1.5k-Se)2 micelles can be more sensitive drug carriers than (PEO2k-b-PFMA1.5k-S)2 micelles. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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32 pages, 11381 KiB  
Article
Smart pH- and Temperature-Sensitive Micelles Based on Chitosan Grafted with Fatty Acids to Increase the Efficiency and Selectivity of Doxorubicin and Its Adjuvant Regarding the Tumor Cells
by Igor D. Zlotnikov, Dmitriy A. Streltsov, Alexander A. Ezhov and Elena V. Kudryashova
Pharmaceutics 2023, 15(4), 1135; https://doi.org/10.3390/pharmaceutics15041135 - 3 Apr 2023
Cited by 11 | Viewed by 1637
Abstract
The main factors that determine the low effectiveness of chemotherapy are the low target bioavailability of antitumor drugs and the efflux process. In attempts to overcome this problem, several approaches are proposed here. Firstly, the development of polymeric micellar systems based on chitosan [...] Read more.
The main factors that determine the low effectiveness of chemotherapy are the low target bioavailability of antitumor drugs and the efflux process. In attempts to overcome this problem, several approaches are proposed here. Firstly, the development of polymeric micellar systems based on chitosan grafted by fatty acids (different types to optimize their properties), which, on the one hand, increase the solubility and bioavailability of cytostatics and, on the other hand, effectively interact with tumor cells due to the polycationic properties of chitosan, allowing for more effective penetration of cytostatic drugs into the cells. Secondly, the use of adjuvants—synergists of cytostatics (such as eugenol) included in the same micellar formulation—that selectively enhance the accumulation and retention of cytostatics in the tumor cells. pH- and temperature-sensitive polymeric micelles developed show high entrapment efficiency for both cytostatics and eugenol (EG) >60% and release the drug in a prolonged manner for 40 h in a weakly acidic medium corresponding to the microenvironment of tumors. In a slightly alkaline environment, the drug circulates longer (more than 60 h). The thermal sensitivity of micelles is realized due to an increase in the molecular mobility of chitosan, which undergoes a phase transition at 32–37 °C. The effect of the cytostatic drug doxorubicin (Dox) on cancerous A549 cells and model healthy cells of human embryonic renal epithelium (HEK293T) was studied by FTIR spectroscopy and fluorescence microscopy. Micellar Dox penetrates into cancer cells 2–3 times more efficiently when using EG adjuvant, which inhibits efflux, as demonstrated by a significant increase in the ratio of intra- and extracellular concentrations of the cytostatic. However, here it is worth remembering about healthy cells that they should not be damaged: according to changes in the FTIR and fluorescence spectra, the penetration of Dox into HEK293T when using micelles in combination with EG is reduced by 20–30% compared to a simple cytostatic. Thus, experimental developments of combined micellar cytostatic drugs have been proposed to increase the effectiveness of cancer treatment and overcome multiple drug resistance. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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13 pages, 1851 KiB  
Article
pH-Responsive Poly(ethylene glycol)-b-poly(2-vinylpyridine) Micelles for the Triggered Release of Therapeutics
by Kyle Brewer, Fengxiang Bai and Anton Blencowe
Pharmaceutics 2023, 15(3), 977; https://doi.org/10.3390/pharmaceutics15030977 - 18 Mar 2023
Cited by 5 | Viewed by 1768
Abstract
The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system—e.g., those utilising poly(ethylene glycol)- [...] Read more.
The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system—e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers—there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46–235 RUs). All copolymers exhibited narrow dispersity values (Đ ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4–4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery—albeit for select, compatible hydrophobic drugs—which warrants their further investigation to develop and evaluate clinically relevant micelle systems. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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14 pages, 3040 KiB  
Article
Synthesis and Characterization of Linear Copolymers Based on Pharmaceutically Functionalized Monomeric Choline Ionic Liquid for Delivery of p-Aminosalicylate
by Shadi Keihankhadiv and Dorota Neugebauer
Pharmaceutics 2023, 15(3), 860; https://doi.org/10.3390/pharmaceutics15030860 - 7 Mar 2023
Cited by 4 | Viewed by 1506
Abstract
Bioactive linear poly(ionic liquid)s (PIL) were designed as carriers in drug delivery systems (DDS). Their synthesis was based on a monomeric ionic liquid (MIL) with a relevant pharmaceutical anion to create therapeutically functionalized monomers, which further can be used in the controlled atom [...] Read more.
Bioactive linear poly(ionic liquid)s (PIL) were designed as carriers in drug delivery systems (DDS). Their synthesis was based on a monomeric ionic liquid (MIL) with a relevant pharmaceutical anion to create therapeutically functionalized monomers, which further can be used in the controlled atom transfer radical polymerization (ATRP). The presence of chloride counterions in the quaternary ammonium groups of choline MIL, e.g., [2-(methacryloyloxy)ethyl]trimethyl-ammonium chloride (ChMACl), was stimulated to undergo the anion exchange with p-aminosalicylate sodium salt (NaPAS) as the source of the pharmaceutical anion with antibacterial activity. The resultant [2-(methacryloyloxy)ethyl]trimethylammonium p-aminosalicylate (ChMAPAS) was copolymerized to attain the well-defined linear choline-based copolymers with various contents of PAS anions (24–42%), which were regulated by the initial ratio of ChMAPAS to MMA and conversion degree. The length of polymeric chains was evaluated by the total monomer conversion (31–66%) yielding degree of polymerization (DPn = 133–272). Depending on the polymer carrier composition, PAS anions were exchanged by 60–100% within 1 h, 80–100% within 4 h, and completely after 24 h by phosphate anions in PBS imitating a physiological fluid. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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16 pages, 2205 KiB  
Article
Revisiting the Solubility–Permeability Relationship with Hydrophobic Drug Umifenovir in Pluronic Solutions: Impact of pH and Co-Solvent
by Tatyana Volkova, Olga Simonova and German Perlovich
Pharmaceutics 2023, 15(2), 422; https://doi.org/10.3390/pharmaceutics15020422 - 27 Jan 2023
Cited by 1 | Viewed by 1326
Abstract
This study describes the influence of pluronic F-127 (F-127) and ethanol (EtOH) on the solubility of umifenovir (UMF) in buffer solutions of pH 2.0 and pH 7.4, and its permeability through cellulose membranes. A 44.4-fold greater UMF solubility in acidic medium as compared [...] Read more.
This study describes the influence of pluronic F-127 (F-127) and ethanol (EtOH) on the solubility of umifenovir (UMF) in buffer solutions of pH 2.0 and pH 7.4, and its permeability through cellulose membranes. A 44.4-fold greater UMF solubility in acidic medium as compared to an alkaline one was estimated at 310.15 K. The concentration of UMF in the saturated solution was enhanced by the interaction with F-127 micelles. The combined positive effect of EtOH and F-127 on the solubility was estimated. The aggregation number of F-127 micelles in the presence of 10% and 20% ethanol appeared to be reduced by 2.1-fold and 4.1-fold, respectively, as compared to buffer pH 7.4. The presence of ethanol in buffer pH 7.4 solution provided better solvent conditions but inhibited the formation of F-127 micelles. The impact of UMF on the aggregation number of F-127 was not pronounced and was expressed only by a slight increase of 1 and 3 units in 10% and 20% EtOH, respectively. According to the values of zeta potential, addition of EtOH reduced the stability of the system. The permeation of UMF in buffer pH 7.4 measured through the cellulose membrane MWCO 12–14 kDa was increased 1.4-fold by 10% EtOH. An increase in EtOH content to 20% reduced this effect to 1.2-fold. Decreasing effect of 1.5% F-127 on the permeability was inhibited by using 10% EtOH. The solution containing 1.5% F-127 and 10% EtOH was shown to be an advantageous system for UMF in view of the solubility–permeability balance. The authors suppose the findings of the study to be useful for the design of pharmaceutical formulations based on UMF antiviral drugs. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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20 pages, 5684 KiB  
Article
A CO2-Responsive Imidazole-Functionalized Fluorescent Material Mediates Cancer Chemotherapy
by Vo Thuy Thien Ngan, Po-Yen Chiou, Fasih Bintang Ilhami, Enyew Alemayehu Bayle, Yeong-Tarng Shieh, Wei-Tsung Chuang, Jem-Kun Chen, Juin-Yih Lai and Chih-Chia Cheng
Pharmaceutics 2023, 15(2), 354; https://doi.org/10.3390/pharmaceutics15020354 - 20 Jan 2023
Cited by 11 | Viewed by 1932
Abstract
We present a breakthrough in the synthesis and development of functional gas-responsive materials as highly potent anticancer agents suitable for applications in cancer treatment. Herein, we successfully synthesised a stimuli-responsive multifunctional material (I-R6G) consisting of a carbon dioxide (CO2)-sensitive imidazole moiety [...] Read more.
We present a breakthrough in the synthesis and development of functional gas-responsive materials as highly potent anticancer agents suitable for applications in cancer treatment. Herein, we successfully synthesised a stimuli-responsive multifunctional material (I-R6G) consisting of a carbon dioxide (CO2)-sensitive imidazole moiety and spirolactam-containing conjugated rhodamine 6G (R6G) molecule. The resulting I-R6G is highly hydrophobic and non- or weakly fluorescent. Simple CO2 bubbling treatment induces hydrophobic I-R6G to completely dissolve in water and subsequently form self-assembled nanoparticles, which exhibit unique optical absorption and fluorescence behaviours in water and extremely low haemolytic ability against sheep red blood cells. Reversibility testing indicated that I-R6G undergoes reversible CO2/nitrogen (N2)-dependent stimulation in water, as its structural and physical properties can be reversibly and stably switched by alternating cycles of CO2 and N2 bubbling. Importantly, in vitro cellular assays clearly demonstrated that the CO2-protonated imidazole moiety promotes rapid internalisation of CO2-treated I-R6G into cancer cells, which subsequently induces massive levels of necrotic cell death. In contrast, CO2-treated I-R6G was not internalised and did not affect the viability of normal cells. Therefore, this newly created system may provide an innovative and efficient route to remarkably improve the selectivity, safety and efficacy of cancer treatment. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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Review

Jump to: Research

49 pages, 5835 KiB  
Review
Polymeric Micellar Systems—A Special Emphasis on “Smart” Drug Delivery
by Irina Negut and Bogdan Bita
Pharmaceutics 2023, 15(3), 976; https://doi.org/10.3390/pharmaceutics15030976 - 17 Mar 2023
Cited by 23 | Viewed by 3702
Abstract
Concurrent developments in anticancer nanotechnological treatments have been observed as the burden of cancer increases every year. The 21st century has seen a transformation in the study of medicine thanks to the advancement in the field of material science and nanomedicine. Improved drug [...] Read more.
Concurrent developments in anticancer nanotechnological treatments have been observed as the burden of cancer increases every year. The 21st century has seen a transformation in the study of medicine thanks to the advancement in the field of material science and nanomedicine. Improved drug delivery systems with proven efficacy and fewer side effects have been made possible. Nanoformulations with varied functions are being created using lipids, polymers, and inorganic and peptide-based nanomedicines. Therefore, thorough knowledge of these intelligent nanomedicines is crucial for developing very promising drug delivery systems. Polymeric micelles are often simple to make and have high solubilization characteristics; as a result, they seem to be a promising alternative to other nanosystems. Even though recent studies have provided an overview of polymeric micelles, here we included a discussion on the “intelligent” drug delivery from these systems. We also summarized the state-of-the-art and the most recent developments of polymeric micellar systems with respect to cancer treatments. Additionally, we gave significant attention to the clinical translation potential of polymeric micellar systems in the treatment of various cancers. Full article
(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery)
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