Copolymers: efficient carriers for intelligent nanoparticulate drug targeting and gene therapy

Copolymers are among the most promising substances used in the preparation of drug/gene delivery systems. Different categories of copolymers, including block copolymers, graft copolymers, star copolymers and crosslinked copolymers, are of interest in drug delivery. A variety of nanostructures, including polymeric micelles, polymersomes and hydrogels, have been prepared from copolymers and tested successfully for their drug delivery potential. The most recent area of interest in this field is smart nanostructures, which benefit from the stimuli-responsive properties of copolymeric moieties to achieve novel targeted drug delivery systems. Different copolymer applications in drug/gene delivery using nanotechnology-based approaches with particular emphasis on smart nanoparticles are reviewed.     

The role of miktoarm star copolymers in drug delivery systems

Abstract

Miktoarm star copolymers are relatively considered to be a new and unique class of macromolecules, and are a new topical area due to the unique properties by varying their polymer arms. This macromolecules with the A_mB_n architecture, have m arms of polymer A and n arms of polymer B connected at one central junction point. Over the past decade, miktoarms have been used in biomedical applications such as drug delivery, gene delivery, tissue engineering, diagnosis, and antibacterial/antifouling biomaterials. The intensified interest in miktoarms is attributed to their unique topological structures and attractive physical/chemical properties, including low critical micelle concentration (CMC) in solutions, encapsulation capability, internal and peripheral functionality, and enhanced stimuli-responsiveness. This review outlines the advances in the use of miktoarms in drug delivery for their good performance in biocompatibility, biodegradability and sustained, controlled and targeted drug delivery during the past decade and some unique self-assembly behaviors of miktoarm star copolymers have been reported.     

Synthesis of click‐reactive HPMA copolymers using RAFT polymerization for drug delivery applications

This study describes a versatile strategy combining reversible addition fragmentation transfer (RAFT) polymerization and click chemistry to synthesize well‐defined, reactive copolymers of N‐(2‐hydroxypropyl)methacrylamide (HPMA) for drug delivery applications. A novel azide containing monomer N‐(3‐azidopropyl)methacrylamide (AzMA) was synthesized and copolymerized with HPMA using RAFT polymerization to provide p(HPMA‐co‐AzMA) copolymers with high control of molecular weight (～10–54 kDa) and polydispersity (≤1.06). The utility of the side‐chain azide functionality by Cu(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) was demonstrated by efficient conjugation (up to 92%) of phosphocholine, a near infrared dye, and poly(ethylene glycol) (PEG) with different substitution degrees, either alone or in combination. This study introduces a novel and versatile method to synthesize well‐defined click‐reactive HPMA copolymers for preparing a panel of bioconjugates with different functionalities needed to systemically evaluate and tune the biological performance of polymer‐based drug delivery. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 5091–5099     

Morphology engineering of a novel poly(L‐lactide)/poly(1,5‐dioxepan‐2‐one) microsphere system for controlled drug delivery

Morphology is presented as a powerful tool to control the in vitro degradation and drug release characteristics of novel drug delivery microspheres prepared from homopolymer blends of 1,5‐dioxepan‐2‐one, DXO, and L ‐lactide, L‐LA. Their performance in this respect was compared to analogous P(L‐LA‐co‐DXO) microspheres. Blends formed denser and less porous microspheres with a higher degree of matrix crystallinity than copolymers of corresponding L‐LA:DXO composition. The morphology differences of blends and copolymers, further adjustable by means of component ratio, are shown to have a vital impact on the in vitro performance. Sustained drug delivery was obtained from both copolymers and blends. Molecular weight loss was retarded and diffusion‐mediated release was inhibited in the latter case, further delaying the release process. The effects of storage on the physicochemical properties of these systems were evaluated under desiccated and moist conditions for 5 months. Storage‐induced physicochemical changes, such as matrix crystallization and molecular weight decrease, were accelerated at higher relative humidities. P(L‐LA‐co‐DXO) demonstrated higher moisture sensitivity than a PLLA‐PDXO blend of corresponding composition. The more crystalline and dense morphology of blend microspheres may thus be considered an improvement of the storage stability. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 786–796, 2000     

Preparation and drug controlled-release of polyion complex micelles as drug delivery systems

Block copolymers, poly(N-vinylprrolidone)-block-poly(styrene-alter-maleic anhydride) (PVP-b-PSMA) and poly(N-vinylprrolidone)-block-poly(N,N-dimethylaminoethyl methacrylate) (PVP-b-PDMAEMA), were synthesized by reversible addition- fragmentation chain transfer (RAFT) polymerization. In aqueous media, this a pair of oppositely-charged diblock copolymers could self-assemble into stable and narrow distribution polyion complex micelles (PICMs). Transmission electron micrographs (TEM) and dynamic light scattering (DLS) analysis showed that the micelles to be spherically shaped with mean hydrodynamic diameter around 70 nm. In addition, the PICMs display ability to response to external stimuli. All of theses features are quite feasible for utilizing it as a novel intelligent drug delivery system. In order to assess its application in biomedical area, release profiles of coenzyme A (Co A) from PICMs were studied under both simulated gastric and intestinal pH conditions. The release was much quicker in pH 7.4 buffer than in pH 2.0 solution. Based on these results, these PICMs could be a potential pH-sensitive carrier for colon-specific drug delivery system.     

Synthesis and properties of polypeptoid-containing block copolymers: A review

Polypeptoids, with similar structure to polypeptides, are nowadays rising stars due to their excellent solubility, processibility, enzymatic stability, and biocompatibility. Attractive properties of polypeptoid-containing copolymers endow them with various applications in surface antifouling, biosensing, microreactor, drug delivery, and stimuli–response. The syntheses of block copolymers containing polypeptoids have attracted a great amount of interest so far. The review summarizes the synthetic strategies of polypeptoid-containing copolymers, that is, polypeptoid-b-polypeptoid, −polypeptide, −polyester, −polyether and -polyolefin developed recently, as well as their phase-separation, assembly and stimuli–response properties.     

Synthesis of Double Hydrophilic Block Copolymers Poly(2-isopropyl-2-oxazoline-b-ethylenimine) and their DNA Transfection Efficiency

Gene delivery is now a part of the therapeutic arsenal for vaccination and treatments of inherited or acquired diseases. Polymers represent an opportunity to develop new synthetic vectors for gene transfer, with a prerequisite of improved delivery and reduced toxicity compared to existing polymers. Here, the synthesis in a two-step's procedure of linear poly(ethylenimine-b-2-isopropyl-2-oxazoline) block copolymers with the linear polyethylenimine (lPEI) block of various molar masses is reported; the molar mass of the poly(2-isopropyl-2-oxazoline) (PiPrOx) block has been set to 7 kg mol⁻¹. Plasmid DNA condensation is successfully achieved, and in vitro transfection efficiency of the copolymers is at least comparable to that obtained with the lPEI of same molar mass. lPEI-b-PiPrOx block copolymers are however less cytotoxic than their linear counterparts. PiPrOx can be a good alternative to PEG which is often used in drug delivery systems. The grafting of histidine moieties on the lPEI block of lPEI-b-PiPrOx does not provide any real improvement of the transfection efficiency. A weak DNA condensation is observed, due to increased steric hindrance along the lPEI backbone. The low cytotoxicity of lPEI-b-PiPrOx makes this family a good candidate for future gene delivery developments.     

Biocompatibility evaluation of self‐assembled micelles prepared from poly(lactide‐co‐glycolide)‐poly(ethylene glycol) diblock copolymers

In this work, a series of PLGA‐PEG diblock copolymers were synthesized by ring‐opening polymerization of L‐lactide and glycolide using mPEG as macroinitiator and stannous octoate as catalyst. Spherical micelles were obtained from the various copolymers by using co‐solvent evaporation method. The biocompatibility of micelles was evaluated with the aim of assessing their potential in the development of drug delivery systems. Various aspects of biocompatibility were considered, including MTT assay, agar diffusion test, release of cytokines, hemolytic test, dynamic clotting time, protein adsorption in vitro, and zebrafish embryonic compatibility in vivo. The combined results revealed that the micelles present good cytocompatibility and hemocompatibility in vitro. Moreover, the cumulative effects of micelles throughout embryos developing stages have no toxicity in vivo. It is thus concluded that micelles prepared from PLGA‐PEG copolymers present good biocompatibility as potential drug carrier.     

Poly(2-oxazoline)-Containing Triblock Copolymers: Synthesis and Applications

This review focuses on poly(2-oxazoline) containing triblock copolymers and their applications. A detailed overview of the synthetic techniques is provided. Triblock copolymers solely based on poly(2-oxazoline)s can be synthesized by sequential monomer addition utilizing mono- as well as bifunctional initiators for the cationic ring-opening polymerization of 2-oxazolines. Crossover and coupling techniques enable access to triblock copolymers comprising, e.g., polyesters, poly(dimethylsiloxane)s, or polyacrylates in combination with poly(2-oxazoline) based segments. Besides systematic studies to develop structure property relationships, these polymers have been applied, e.g., in drug delivery, as (functionalized) vesicles, in segmented networks or as nanoreactors.     

Synthesis of linear and star‐like poly(ε‐caprolactone)‐b‐poly{γ‐2‐[2‐(2‐methoxy‐ethoxy)ethoxy]ethoxy‐ε‐caprolactone} amphiphilic block copolymers using zinc undecylenate

Linear and star‐like amphiphilic diblock copolymers were synthesized by the ring‐opening polymerization of ε‐caprolactone and γ‐2‐[2‐(2‐methoxyethoxy)ethoxy]ethoxy‐ε‐caprolactone monomers using zinc undecylenate as a catalyst. These polymers have potential applications as micellar drug delivery vehicles, therefore the properties of the linear and 4‐arm star‐like structures were examined in terms of their molecular weight, viscosity, thermodynamic stability, size, morphology, and drug loading capacity. Both the star‐like and linear block copolymers showed good thermodynamic stability and degradability. However, the star‐like polymers were shown to have increased stability at lower concentrations with a critical micelle concentration (CMC) of 5.62 × 10^?4 g L^?1, which is less than half the concentration of linear polymer needed to form micelles. The star‐like polymeric micelles showed smaller sizes when compared with their linear counterparts and a higher drug loading capacity of doxorubicin, making them better suited for drug delivery purposes. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3601–3608     

Target grafting of poly(2-(dimethylamino)ethyl methacrylate) to biodegradable block copolymers

A series of copolymers composed of methoxy poly(ethylene glycol) and a hydrophobic block of poly(ɛ-caprolactone-co-propargyl carbonate) grafted with poly(2-[dimethylamino]ethyl methacrylate) was synthesized by combining ring opening polymerization, azide-alkyne click reaction, and atom transfer radical polymerization (ATRP). Well-defined copolymers with a target composition and a tailored structure were achieved via the grafting from approach by using a single catalytic system for both click reaction and ATRP. Kinetic studies demonstrated the controlled/living character of the employed polymerization methods. The thermal properties and self-assembly in aqueous medium of the graft copolymers were dependent on their composition. The resulting polymeric materials showed low cytotoxicity toward L929 cells, demonstrating their potential for biomedical applications. This type of materials containing cationic side chains tethered to biocompatible and biodegradable segments could be the basis for promising candidates as drug and gene delivery systems.     

Synthesis and self‐assembly of thermosensitive double‐hydrophilic poly(N‐vinylcaprolactam)‐b‐poly(N‐vinyl‐2‐pyrrolidone) diblock copolymers

We report on novel diblock copolymers of poly(N‐vinylcaprolactam) (PVCL) and poly(N‐vinyl‐2‐pyrrolidone) (PVPON) (PVCL‐b‐PVPON) with well‐defined block lengths synthesized by the MADIX/reversible addition‐fragmentation chain transfer (RAFT) process. We show that the lower critical solution temperatures (LCST) of the block copolymers are controllable over the length of PVCL and PVPON segments. All of the diblock copolymers dissolve molecularly in aqueous solutions when the temperature is below the LCST and form spherical micellar or vesicular morphologies when temperature is raised above the LCST. The size of the self‐assembled structures is controlled by the molar ratio of PVCL and PVPON segments. The synthesized homopolymers and diblock copolymers are demonstrated to be nontoxic at 0.1–1 mg mL^?1 concentrations when incubated with HeLa and HEK293 cancer cells for various incubation times and have potential as nanovehicles for drug delivery. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2725–2737     

Poly(2-(dimethylamino)ethyl methacrylate)-b-poly(hydroxypropyl methacrylate) copolymers/bovine serum albumin complexes in aqueous solutions

Complexation ability of poly(2-(dimethylamino)ethyl methacrylate)-b-poly(hydroxy propyl methacrylate) (PDMAEMA-b-PHPMA) amphiphilic doubly thermo-responsive block copolymers, and their quaternized counterparts QPDMAEMA-b-PHPMA, toward bovine serum albumin (BSA) is studied in aqueous solutions. The PDMAEMA-b-PHPMA amphiphilic block copolymers self-assemble in nanostructured aggregates with PDMAEMA coronas having different inner structure and micro-polarity depending on the solubilization protocol utilized when inserted in aqueous media. By incorporating different BSA concentrations, we investigate the copolymer–protein interactions by light scattering measurements in aqueous solutions in a broad temperature range, utilizing different solubilization protocols for the copolymers. Fluorescence spectroscopy and ζ-potential measurements were also utilized to investigate the structure and properties of the copolymer/protein complexes formed in each case. Such knowledge may lead to a better understanding of the inner structure and micro polarity of the nanostructured aggregates formed by the novel (Q)PDMAEMA-b-PHPMA copolymers, along with their potential abilities in nanocarrier formation, protein complexation, stabilization, and delivery.     

Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery. Supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No.20060358036)     

Poly(2-[dimethylamino]ethyl methacrylate)-b-poly(hydroxypropyl methacrylate)/DNA polyplexes in aqueous solutions

This study involves the investigation of the complexation ability of poly(2-[dimethylamino]ethyl methacrylate)-b-poly(hydroxypropyl methacrylate) (PDMAEMA-b-PHPMA) amphiphilic pH and thermoresponsive block copolymers, and their quaternized counterparts QPDMAEMA-b-PHPMA, toward short DNA in aqueous solutions. The PDMAEMA-b-PHPMA amphiphilic block copolymers present various self-assembly characteristics when inserted into aqueous media, depending on the composition, the solubilization protocol, the acidity and the temperature of the aqueous media. Copolymer aggregates-DNA interactions and nanostructure formation after complexation are investigated by dynamic light scattering and intensity measurements in aqueous solutions in a fixed temperature range, utilizing two different solubilization protocols for the copolymers. Ethidium bromide assays by fluorescence spectroscopy and ζ-potential measurements were also utilized to investigate the structure and properties of the DNA/copolymer polyplexes. The interpretation of such physicochemical characterization provides extra comprehension of the novel (Q)PDMAEMA-b-PHPMA copolymers self-assembly characteristics and assesses their ability for DNA complexation, stabilization, and delivery.     

Tuning salicylate‐based polymers to overcome lag time and extend release via copolymers and polymer blends

This work describes how physicochemical properties of salicylate‐based poly(anhydride‐esters) (PAEs) can be tuned for drug delivery and optimized by comparing copolymerization with polymer blending. These alterations reduced the lag time of drug release, while still maintaining a long‐term drug release profile. The chemical composition of the copolymers and polymer blends was determined by proton nuclear magnetic resonance and additional properties such as molecular weight, glass transition temperature and contact angle measurements were obtained. In vitro salicylic acid release from the copolymers and blends is studied in an environment mimicking physiological conditions. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 685–689     

Synthesis and self‐assembly of thermoresponsive poly(N‐isopropylacrylamide)‐b‐poly(oligo ethylene glycol methyl ether acrylate) double hydrophilic block copolymers

We report on the synthesis of novel poly(N‐isopropylacrylamide)‐b‐poly(oligo ethylene glycol methyl ether acrylate) (PNIPAM‐b‐POEGA) thermoresponsive block copolymers using reversible addition–fragmentation chain transfer polymerization methodologies. The synthesized block copolymers are characterized by gel permeation chromatography, nuclear magnetic resonance, Fourier transform infrared (FTIR) techniques in terms of molecular weight and composition. Their thermoresponsive self‐assembly in aqueous media is investigated using dynamic and static light scattering. The PNIPAM‐b‐POEGA thermoresponsive block copolymers formed aggregates in water by increasing the temperature above the lower critical solution temperature value of PNIPAM block. Solution pH seems to affect the self‐assembly behavior in some cases due to the presence of ? COOH end groups. Therefore, the copolymers were utilized as “smart” nanocarries for the hydrophobic drug indomethacin, implementing a novel encapsulation protocol taking advantage of the thermoresponsive character of the PNIPAM block. The empty and loaded self‐assembled nanocarriers systems were studied by light scattering techniques, ultraviolet–visible, and FTIR spectroscopy, which gave information on the size and structure of the nanocarriers, the drug loading content and the interactions between the drug and the components of the block copolymers. Drug loaded nanostructures show stability at room temperature, due to active drug/block copolymer interactions. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1467–1477     

Stimuli‐responsive amphiphilic PDMAEMA‐b‐PLMA copolymers and their cationic and zwitterionic analogs

In this work, the synthesis and characterization of novel amphiphilic diblock copolymers of poly(2‐dimethylamino ethyl methacrylate)‐b‐poly(lauryl methacrylate), PDMAEMA‐b‐PLMA, using the reversible addition‐fragmentation chain transfer (RAFT) polymerization technique, are reported. The diblocks were successfully derivatized to cationic and zwitterionic block polyelectrolytes by quaternization and sulfobetainization of the PDMAEMA block, respectively. Furthermore, their molecular and physicochemical characterization was performed by using characterization techniques such as NMR and FTIR, size exclusion chromatography, light scattering techniques, and transmission electron microscopy. The structure of the diblock micelles, their behavior, and properties in aqueous solution were investigated under the effect of pH, temperature, and ionic strength, as PDMAEMA and its derivatives are stimuli‐responsive polymers and exhibit responses to variations of at least one of these physicochemical parameters. These new families of stimuli‐responsive block copolymers respond to changes of their environment giving interesting nanostructures, behavioral motifs, and properties, rendering them useful as nanocarriers for drug delivery and gene therapy. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 598–610     

Reduction and pH dual‐responsive block copolymers containing pendent p‐nitrobenzyl carbamate functionalities: Synthesis and self‐assembly behavior

We report on the preparation of reduction‐responsive amphiphilic block copolymers containing pendent p‐nitrobenzyl carbamate (pNBC)‐caged primary amine moieties by reversible addition–fragmentation chain transfer (RAFT) radical polymerization using a poly(ethylene glycol)‐based macro‐RAFT agent. The block copolymers self‐assembled to form micelles or vesicles in water, depending on the length of hydrophobic block. Triggered by a chemical reductant, sodium dithionite, the pNBC moieties decomposed through a cascade 1,6‐elimination and decarboxylation reactions to liberate primary amine groups of the linkages, resulting in the disruption of the assemblies. The reduction sensitivity of assemblies was affected by the length of hydrophobic block and the structure of amino acid‐derived linkers. Using hydrophobic dye Nile red (NR) as a model drug, the polymeric assemblies were used as nanocarriers to evaluate the potential for drug delivery. The NR‐loaded nanoparticles demonstrated a reduction‐triggered release profile. Moreover, the liberation of amine groups converted the reduction‐responsive polymer into a pH‐sensitive polymer with which an accelerated release of NR was observed by simultaneous application of reduction and pH triggers. It is expected that these reduction‐responsive block copolymers can offer a new platform for intracellular drug delivery. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1333–1343     

PEO-PPO-PEO在生物医用材料方面的研究进展

聚氧乙烯-聚氧丙烯-聚氧乙烯三嵌段共聚物因其具有良好的生物相容性和蛋白抗性,近年来在生物医用材料中的应用越来越广泛.聚氧乙烯-聚氧丙烯-聚氧乙烯水溶液具有温度敏感的胶束化和热可逆凝胶化特点,被认为是一种具有许多优点的药物传输载体,药物与胶束的核心结合增加了药物的溶解性、代谢稳定性和体内循环时间.本文对聚氧乙烯-聚氧丙烯-聚氧乙烯在生物医用方面的研究进展进行了综述,并重点介绍了其在药物传输载体,组织工程等方面的研究进展.