Advances in mucoadhesion and mucoadhesive polymers

Mucoadhesion is the ability of materials to adhere to mucosal membranes in the human body and provide a temporary retention. This property has been widely used to develop polymeric dosage forms for buccal, oral, nasal, ocular and vaginal drug delivery. Excellent mucoadhesive properties are typical for hydrophilic polymers possessing charged groups and/or non-ionic functional groups capable of forming hydrogen bonds with mucosal surfaces. This feature article considers recent advances in the study of mucoadhesion and mucoadhesive polymers. It provides an overview on the structure of mucosal membranes, properties of mucus gels and the nature of mucoadhesion. It describes the most common methods to evaluate mucoadhesive properties of various dosage forms and discusses the main classes of mucoadhesives.     

High Molecular Weight Poly(ethylenimine)‐Based Water‐Soluble Lipopolymer for Transfection of Cancer Cells

Over the past decade, search for novel materials for nucleic acid delivery has prompted a special interest in polymeric nanoparticles (NPs). In this study, the biological applicability of a water‐soluble cationic lipopolymer (WSLP) obtained by the modification of high molecular weight branched poly(ethylenimine) (PEI) with cholesteryl chloroformate is characterized and assessed for better cellular membrane permeability. To test the delivery efficiency of the produced lipopolymer, plasmid DNA (pDNA) encoding the enhanced green fluorescent protein and WSLP are mixed at different charge ratios. WSLP and WSLP/pDNA complexes are characterized by dynamic and static light scattering, particle charge detection, scanning electron microscopy, and transmission electron microscopy. The pDNA loading of WSLP is also verified by agarose gel electrophoresis. Cytotoxicity of PEI, WSLP, and of WSLP/pDNA is evaluated on human A549 and HeLa cells. A remarkable dependence of the toxicity on the dose, cholesterylation, and charge ratio is detected. Transfection is monitored by flow cytometry and by fluorescence microscopy. Importantly, cholesterylation decreases the toxicity of the polymer, while promoting high transfection efficiency in both cell lines. This work indicates a possible optimization mode of the high molecular weight PEI‐based WSLP rendering it a promising candidate for gene delivery.     

Synthesis,self‐assembly and recognition properties of biomimetic star‐shaped poly(ε‐caprolactone)‐b‐glycopolymer block copolymers

Biomimetic star‐shaped poly(ε‐caprolactone)‐b‐poly(gluconamidoethyl methacrylate) block copolymers (SPCL‐PGAMA) were synthesized from the atom transfer radical polymerization (ATRP) of unprotected GAMA glycomonomer using a tetra(2‐bromo‐2‐methylpropionyl)‐terminated star‐shaped poly(ε‐caprolactone) (SPCL‐Br) as a macroinitiator in NMP solution at room temperature. The block length of PGAMA glycopolymer within as‐synthesized SPCL‐PGAMA copolymers could be adjusted linearly by controlling the molar ratio of GAMA glycomonomer to SPCL‐Br macroinitiator, and the molecular weight distribution was reasonably narrow. The degree of crystallization of PCL block within copolymers decreased with the increasing block length ratio of outer PGAMA to inner PCL. Moreover, the self‐assembly properties of the SPCL‐PGAMA copolymers were investigated by NMR, UV‐vis, DLS, and TEM, respectively. The self‐assembled glucose‐installed aggregates changed from spherical micelles to worm‐like aggregates, then to vesicles with the decreasing weight fraction of hydrophilic PGAMA block. Furthermore, the biomolecular binding of SPCL‐PGAMA with Concanavalin A (Con A) was studied by means of UV‐vis, fluorescence spectroscopy, and DLS, which demonstrated that these SPCL‐PGAMA copolymers had specific recognition with Con A. Consequently, this will not only provide biomimetic star‐shaped SPCL‐PGAMA block copolymers for targeted drug delivery, but also improve the compatibility and drug release properties of PCL‐based biomaterials for hydrophilic peptide drugs. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 817–829, 2008     

Recent developments in intelligent biomedical polymers

Intelligent polymers or stimuli-responsive polymers may exhibit distinct transitions in physical-chemical properties, including conformation, polarity, phase structure and chemical composition in response to changes in environmental stimuli. Due to their unique 'intelligent' characteristics, stimuli-sensitive polymers have found a wide variety of applications in biomedical and nanotechnological fields. This review focuses on the recent developments in biomedical application of intelligent polymer systems, s...     

Synthesis and properties of monocleavable amphiphilic comblike copolymers with alternating PEG and PCL grafts

Symmetric reduction‐responsive amphiphilic comblike copolymers mid‐disulfide‐functionalized comblike copolymers with alternating copolymer comprised of styrenic unit and N‐(2‐hydroxyethyl) maleimide (HEMI) unit (poly(St‐alt‐HEMI)) backbones and alternating PEG and PCL side chains (S‐CP(PEG‐alt‐PCL)) with poly(St‐alt‐HEMI) backbones and alternating poly(ε‐caprolactone) (PCL) and poly(ethylene glycol) (PEG) side chains were synthesized and used as nanocarriers for in vitro release of doxorubicin. The target copolymers with predetermined molecular weight and narrow molecular weight distribution (M_w/M_n = 1.15–1.20) were synthesized by reversible addition‐fragmentation chain transfer (RAFT) copolymerization of vinylbenzyl‐terminated PEG and N‐(2‐hydroxyethyl) maleimide mediated by a disulfide‐functionalized RAFT agent S‐CPDB, and followed by ring‐opening polymerization of ε‐caprolactone. When compared with linear block copolymer comprised of poly(ethylene glycol) (PEG) and poly(?‐caprolactone) (PCL) segments (PEG‐b‐PCL) copolymers, comblike copolymers with similar PCL contents usually exhibited decreased crystallization temperature, melting temperature, and degree of crystallinity, indicating the significant influence of copolymer architecture on physicochemical properties. Dynamic light scattering measurements revealed that comblike copolymers were liable to self‐assemble into aggregates involving vesicles and micelles with average diameter in the range of 56–226 nm and particle size distribution ranging between 0.07 and 0.20. In contrast to linear copolymer aggregates, comblike copolymer aggregates with similar compositions were of improved storage stability and enhanced drug‐loading efficiency. In vitro drug release confirmed the disulfide‐linked comblike copolymer aggregates could rapidly release the encapsulated drug when triggered by 10 mM DL ‐dithiothreitol. These reduction‐sensitive, biocompatible, and biodegradable aggregates have a potential as controlled delivery vehicles. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Dispersion polymerization of vinyl monomers in supercritical carbon dioxide in the presence of drug molecules: A one‐pot route for the preparation of controlled delivery systems

The polymerization of 1‐vinyl‐2‐pyrrolidone in supercritical carbon dioxide in the presence of ibuprofen as a model drug was investigated as a new one‐pot process for the preparation of polymer‐based drug delivery systems (DDSs). The composites were prepared at 65 °C and P = 31–42 MPa by changing the initial concentration of the drug and the concentration of a crosslinking agent and that of a hydrophobic comonomer. The effects of these parameters on the performances of the polymerization and on the in vitro release kinetics of ibuprofen were studied. In all the experiments, part of the drug was entrapped inside the polymer particles and dissolved more slowly with respect to the pure compound. Copolymerization with methyl methacrylate was the most effective route to obtain a DDS with sustained temporal release of the drug molecule. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7429–7446, 2008     

Conjugates of Antibody‐Targeted PEG Multiblock Polymers with Doxorubicin in Cancer Therapy

The synthesis and physico‐chemical characterisation of biodegradable multiblock polymer drug carriers based on poly(ethylene glycol) (PEG) are described. The blocks of PEG ( = 2 000) are interconnected by an enzymatically degradable tripeptide derivative consisting of one Lys and two Glu residues. An anticancer drug, doxorubicin (Dox), was attached to the polymer carrier by a Gly‐Phe‐Leu‐Gly tetrapeptide spacer, which is also susceptible to degradation by lysosomal enzymes. A targeting polyclonal antibody was covalently linked to the polymer‐Dox conjugate by the aminolytic reaction of reactive sulfosuccinimidyl ester groups of the polymer with the protein. The resulting antibody‐polymer‐drug conjugates were characterised by SEC, UV/VIS spectrophotometry and amino acid analysis. Although the studied polymers show only a moderate antiproliferative activity against concanavalin A‐stimulated murine splenocytes and a murine T‐cell EL 4 lymphoma in vitro, they exhibited significant antitumour efficiency against murine T‐cell EL 4 lymphoma in vivo.

     

Self-assembling viral mimetics: one long journey with short steps

Recently, the Foresight Institute has pronounced six economic challenges that can be addressed through the progress of nanotechnology. One of these is the health and longevity of human life. Amongst applications anticipated to provide a solution to this challenge, gene therapy appears to be particularly promising. In theory, many diseases that result from genetic disorders can be cured by correcting defective genes. In practice, finding efficient and safe delivery vectors remains the stumbling point on the path of genetic therapies to the clinic. Viruses, otherwise the most efficient transfectors, pose safety concerns over immune reactions, whereas synthetic gene packages greatly lack the structural integrity of viruses. An ideal vector is therefore seen as a compromise between the two: a nanoscale device, which would mimic a virus and act as a virus, but would do this at the designer's whim. A strategy to achieve this is offered by the virus architecture itself, the principles of which are translated into the function via exquisitely reproducible self-assembly mechanisms. Thus, to mimic a virus is to mimic the way it is built, i.e., self-assembly. With just a few attempts made so far, the journey to an artificial virus has had a short lifetime, but the promise it holds is not expected to reduce any time soon.     

Amphiphilic cationic [dendritic poly(L-lysine)]-block-poly(L-lactide)-block-[dendritic poly(L-lysine)]s in aqueous solution: self-aggregation and interaction with DNA as gene delivery carriers

A new series of triblock [dendritic poly(L-lysine)]-block-PLLA-block-[dendritic poly(L-lysine)]s (DL(2) -PLLA-DL(2) ) with PLLA block lengths of 11.5-26.5 and double 2-generation PLL dendrons DL(2) as model cationic amphiphiles were synthesized and characterized. Their CAC, self-aggregation and plasmid DNA binding affinities in pure water and PBS were studied. The PLLA block length dependence of particle size, morphology and ξ potential for organized pDNA/amphiphile polyplex aggregates were examined. Finally, toxicities of these DL(2) -PLLA-DL(2) amphiphiles and their polyplexes were assayed by MTT with HeLa, SMMC-7721 and COS-7 cells, and COS-7 cell luciferase and eGFP gene transfection efficacies with these amphiphiles as the delivery carriers were investigated.     

Bioreducible and core‐crosslinked hybrid micelles from trimethoxysilyl‐ended poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide) block copolymers: Thiol‐ene click synthesis and properties

Bioreducible and core‐crosslinked hybrid micelles were for the first time fabricated from biodegradable and biocompatible trimethoxysilyl‐terminated and disulfide‐bond‐linked block copolymers poly(ε‐caprolactone)‐S‐S‐poly(ethylene oxide), which were prepared by combining thiol‐ene coupling reaction and ring‐opening polymerization. The molecular structures, physicochemical, self‐assembly, and bioreducible properties of these copolymers were thoroughly characterized by means of FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide‐angle X‐ray diffraction, dynamic light scattering (DLS), and transmission electron microscopy. The core‐crosslinking sol‐gel reaction was confirmed by ¹H NMR, and the core‐crosslinked hybrid micelles contained about 3 wt % of silica. The bioreducible property of both uncrosslinked and core‐crosslinked micelles in 10 mM 1,4‐dithiothreitol (DTT) solution was monitored by DLS, which demonstrated that the PEO corona gradually shedded from the PCL core. The anticancer doxorubicin drug‐loaded micelles showed nearly spherical morphology compared with blank micelles, presenting a DTT reduction‐triggered drug‐release profile at 37 °C. Notably, the core‐crosslinked hybrid micelles showed about twofold drug loading capacities and a half drug‐release rate compared with the uncross‐liked counterparts. This work provides a useful platform for the fabrication of bioreducible and core‐crosslinked hybrid micelles potential for anticancer drug delivery system. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Temperature responsive copolymers of N‐vinylcaprolactam and di(ethylene glycol) methyl ether methacrylate and their interactions with drugs

Poly(N‐vinylcaprolactam) (PVCL) and poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) are well known for their thermoresponsive behavior in aqueous solutions. Indeed, they display lower critical solution temperatures (LCST) in the physiological range, which makes them interesting for biomedical devices and use in drug delivery systems. Homopolymers of N‐vinylcaprolactam and di(ethylene glycol) methyl ether methacrylate as well as copolymers thereof were synthesized by solution and direct miniemulsion polymerizations. The cloud points of the copolymers in aqueous solution were investigated as a function of temperature, comonomer ratio, and in the presence of model pharmaceutical ingredients. By variation of the comonomer ratio, it was possible to control the cloud point temperature between 26 and 35 °C, which was found to be beneficial to attenuate the effect of the drugs that also altered the cloud points. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3308–3313     

Molecularly Imprinted Polymers: Compromise between Flexibility and Rigidity for Improving Capture of Template Analogues

New synthetic strategies for molecularly imprinted polymers (MIPs) were developed to mimic the flexibility and mobility exhibited by receptor/enzyme binding pockets. The MIPs were prepared by bulk polymerization with quercetin as template molecule, acrylamide as functional monomer, ethylene glycol dimethacrylate as cross‐linker, and THF as porogen. The innovative grafting of specific oligoethylene glycol units onto the imprinted cavities allowed MIPs to be obtained that exhibit extended selectivity towards template analogues. This synthetic strategy gives promising perspectives for the design of molecular recognition of molecules based on a congruent pharmacophore, which should be of interest for drug development.     

New Insight into the Synthesis and Biological Activity of the Polymeric Materials Consisting of Folic Acid and β‐Cyclodextrin

This work presents a very new look at folate targeting and is focused on synthesizing and assessing the biological activity of folic acid‐targeted drug delivery materials based on β‐cyclodextrin. Both folic acid and β‐cyclodextrin have been covalently conjugated to branched polyethylenimine as the polymeric vector. Host–guest inclusion of folic acid into a β‐cyclodextrin cavity, demonstrated by means of the spectroscopic methods (2‐D NMR, IR, UV–Vis), is found to be of crucial importance for biological activity of nanotherapeutics. This paper describes the very first example of the versatile synthetic approach to create the polymeric biosystems, where folic acid activity is not limited by the inclusion phenomenon. Cytotoxicity of the obtained polymeric materials against Lewis lung carcinoma cells is determined by neutral red uptake assay. Folate receptor‐binding studies reveal that the developed synthetic approach enables full exploitation of the potential of folic acid as a targeting ligand.     

仿生微胶囊的组装及其应用

在生物物理和生物医药研究领域中,在分子水平上组装功能化的仿生微胶囊具有重要的理论和应用价值.在现有制备微胶囊的技术手段中,层层组装技术以其能够控制胶囊的尺寸、形状、囊壁的厚度和组成以及易于实现功能化等特点,引起了人们越来越多的研究兴趣.本文将着重介绍如何利用层层组装技术,以磷脂、蛋白质和其他生物大分子为组装基元构筑仿生微胶囊、以及如何将微胶囊进行生物界面化的修饰.此外,以仿生微胶囊为药物载体,探讨其在光动力治疗方面的应用也作简单介绍.     

NIPAAm-containing amphiphilic block copolymers with tailored LCST: Aggregation behavior,cytotoxicity and evaluation as carriers of indomethacin,tetracycline and doxorubicin

Nanocarriers based on amphiphilic block copolymers, with tailored temperature and pH responsiveness, were prepared. The hydrophilic blocks consist of temperature-sensitive [N-isopropylacrylamide (NIPAAm)] or NIPAAm plus pH-sensitive units [5-methacryloyloxy pentatonic acid (5MPA) or 4-methacryloyloxy benzoic acid (4MBA)], while the hydrophobic block is composed of n-hexyl acrylate (HA) or styrene (ST). Particle sizes were within the suitable range for the desired application (30–182?nm). Drug loading was achieved via an organic solvent-free method and a THF-buffer method leading to drug loadings of indomethacin, tetracycline and doxorubicin of up to 11, 11 and 60?wt%, respectively. In vitro release kinetics were performed under simulated physiological conditions (pH 7.4 and 37?°C; pH 6.0 and 40?°C) and show differences depending on the copolymer composition. The average kinetic data were well fitted to the mathematical model of Peppas. NIPAAm-containing copolymers were slight or non-cytotoxic for rat primary hepatocytes at concentrations less than 200?µg mL^?1. Some of the polymeric aggregates prepared may find application as pharmaceutical carriers.     

Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Effect of PLGA block molecular weight on gelling temperature of PLGA‐PEG‐PLGA thermoresponsive copolymers

Thermoresponsive, biodegradable polymeric hydrogel networks are used widely in medicinal applications. Poly(d ,l ‐lactic acid‐co‐glycolic acid)‐b‐poly(ethylene glycol)‐b‐poly(d ,l ‐lactic acid‐co‐glycolic acid) (PLGA‐PEG‐PLGA) triblock copolymers exhibit a sol–gel transition upon heating. The effect of PLGA block and PEG chain molecular weights (MWs) on the gelling temperature of polymer aqueous solution (20% w/w) is described. All polymer solutions convert into a hard gel within 2 °C of the gelling temperature. The release properties of the gels were displayed using paracetamol as a representative drug. A linear relation is described between the gelling temperature and PLGA block MW. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 35–39     

Highly efficient intracellular drug delivery with a negatively charged hyperbranched polysulfonamine

Efficient intracellular translocation is achieved using an easily prepared hyperbranched polysulfonamine that remains negatively charged at physiological pH. Investigations on the cellular uptake mechanism and the subcellular distribution of PSA are reported. The in vitro cytotoxicity of PSA is found to be low. Using doxorubicin as a model drug, a PSA/drug complex is prepared by electrostatic interaction with a high drug payload that exhibits a controlled release in response to pH. Efficient intracellular drug delivery, strong growth inhibition of tumor cells, and low cytotoxicity to normal cells are observed. The results suggest a possible way to utilize anionic polymers for intracellular delivery of therapeutic moieties or drugs.