Suresh K. Jewrajka

Effect of Polyethylene Glycol on Properties and Drug Encapsulation–Release Performance of Biodegradable/Cytocompatible Agarose–Polyethylene Glycol–Polycaprolactone Amphiphilic Co-Network Gels

We synthesized agarose-polycaprolactone (Agr-PCL) bicomponent and Agr-polyethylene glycol-PCL (Agr-PEG-PCL) tricomponent amphiphilic co-network (APCN) gels by the sequential nucleophilic substitution reaction between amine-functionalized Agr and activated halide terminated PCL or PCL-b-PEG-b-PCL copolymer for the sustained and localized delivery of hydrophilic and hydrophobic drugs. The biodegradability of the APCNs was confirmed using lipase and by hydrolytic degradation. These APCN gels displayed good cytocompatibility and blood compatibility. Importantly, these APCN gels exhibited remarkably high drug loading capacity coupled with sustained and triggered release of both hydrophilic and hydrophobic drugs. PEG in the APCNs lowered the degree of phase separation and enhanced the mechanical property of the APCN gels. The drug loading capacity and the release kinetics were also strongly influenced by the presence of PEG, the nature of release medium, and the nature of the drug. Particularly, PEG in the APCN gels significantly enhanced the 5-fluorouracil loading capacity and lowered its release rate and burst release. Release kinetics of highly water-soluble gemcitabine hydrochloride and hydrophobic prednisolone acetate depended on the extent of water swelling of the APCN gels. Cytocompatibility/blood compatibility and pH and enzyme-triggered degradation together with sustained release of drugs show great promise for the use of these APCN gels in localized drug delivery and tissue engineering applications.

Degradable/cytocompatible and pH responsive amphiphilic conetwork gels based on agarose-graft copolymers and polycaprolactone

Amphiphilic conetwork (APCN) gels have emerged as an important class of biomaterials due to their diverse applications. APCN gels based on biocompatible/biodegradable polymers are useful for controlled release and tissue engineering applications. Herein, we report a facile synthesis of APCN gel films by click type sequential nucleophilic substitution reaction between pendent tertiary amine groups of agarose-g-poly(methyl methacrylate)-b(co)-poly(2-dimethylamino)ethyl methacrylate [Agr-g-PMMA-b(co)-PDMA] copolymers and activated benzyl chloride groups of polychloromethyl styrene or benzyl methyl chloride terminated polycaprolactone. A linear triblock copolymer (PDMA-b-PMMA-b-PDMA) containing a central PMMA block and end PDMA blocks was also employed for the synthesis of APCN gels for comparison purposes. These APCN gels exhibit co-continuous nanophase morphology, pH responsive water swelling and pH triggered release of hydrophobic and hydrophilic drugs. These gels are biodegradable/cytocompatible as confirmed by MTT assay and hemolysis experiment. The degraded species undergo micellization in aqueous environment and display a low critical micelle concentration. Milled APCN gel particles are injectable through a hypodermic syringe. This synthesis approach is extremely useful for the preparation of a library of APCN gels of diverse architectures and compositions for biomedical applications.

Self-assembly of modified rhodamine-6G with tri-block copolymer: unusual vesicle formation, pH sensing and dye release properties

A new rhodamine-6G derivative having a C18-alkyl chain self-assembles with an amphiphilic tri-block copolymer and forms stable vesicles in water or in water-ethanol (4 : 1, v/v) medium. The stability of the spirolactam form of the rhodamine-6G derivative in these vesicular structures, along with studies of controlled dye release and pH sensing are discussed. Transmission electron micrographs and DLS analyses confirm the formation of vesicular structures. Atomic force microscopy (AFM) images show that the self assembled tri-block copolymer-octadecyl rhodamine vesicles form near spherical nanostructures with a size ranging from 80 to 110 nm. Furthermore, the vesicular system is disassembled under acidic conditions, releasing the cargo which are an integral part of the vesicle. Dye-release studies showed that the release rates of the loaded dye in the vesicles could be well-controlled as a function of the media pH. These results offer an opportunity to use these nanovesicles as imaging reagents for probing media pH with their simultaneous use as nanocarriers for intracellular drug delivery.

Tailoring polyamide thin film composite nanofiltration membranes by polyethyleneimine and its conjugates for the enhancement of selectivity and antifouling property

Herein, we report a suitable surface modification process for a state-of-art poly(piperazineamide) thin film composite (TFC) nanofiltration (NF) membrane by polyethyleneimine (PEI) and its conjugates (PEI–polyethylene glycol and PEI–dextran) for the enhancement of monovalent ion to divalent ion selectivity and antifouling properties. The nascent TFC NF membrane was treated with PEI and its conjugates for the purpose of modification. The modified membranes exhibited high rejection of divalent cations (88–91%), high rejection of divalent anions (85–92%) and low rejection of NaCl (30–50%). The membranes modified under optimized conditions exhibited considerably enhanced antifouling/anti-scaling properties, similar permeate flux, similar Na+ to SO42− selectivity and much better Na+ to Mg2+ selectivity compared to that of the pristine membrane during the desalination of water containing a mixture of salts and real seawater. The adjustment in permeation property and improvement in antifouling behaviour are attributed to the adjustment of surface charge and pore size by the incorporation of multi-amine containing antifouling polyethylene glycol or dextran on the membrane surface via the post modification process.

Self-assembly of model graft copolymers of agarose and weak polyelectrolyte-based amphiphilic diblock copolymers: Controlled drug release and degradation†

Polysaccharide-based copolymers are promising biomaterials due to their biocompatibility and biodegradability. For potential biomedical applications the copolymer as a whole and all the degraded species must be biocompatible and easily removable from the system. In this regards, new model pH-responsive seaweed agarose (Agr) grafted with weak polyelectrolyte-based well-defined amphiphilic block copolymers ca. poly[(methyl methacrylate)-b-(2-dimethylamino)ethyl methacrylate)] (PMMA-b-PDMA) were designed and synthesized to study the self-assembly, degradation, and in vitro hydrophobic/hydrophilic drug release behavior. The graft copolymer solutions display extremely low critical micelle concentration (CMC) and form pH responsive stable micelles. The degradation study of the graft copolymer reveals that the entire degraded components are well soluble/dispersible in water due to formation of mixed micelles. The micelles are also strongly adsorbed on the mica surface owing to electrostatic interaction. One application of the graft copolymer micelles is that it can entrap both hydrophilic and poorly water soluble hydrophobic drugs effectively and exhibit slow release kinetics. The release kinetics of both the hydrophilic and poorly water soluble hydrophobic drugs change with pH as well as with the composition of the graft copolymer.

Multifunctionalization of Poly(vinylidene fluoride)/Reactive Copolymer Blend Membranes for Broad Spectrum Applications

Simultaneous immobilization and cross-linking of antifouling/low toxic polymers, e.g., poly(ethylenimine) (PEI), dextran (Dex), agarose (Agr), poly(ethylene glycol) (PEG), PEI-Dex, and PEI-PEG conjugates, and stimuli-responsive copolymers on a porous membrane surface in mild reaction conditions is desirable for the enhancement of hydrophilicity, antifouling character, cytocompatibility, and inducing stimuli-responsive behavior. Grafting to technique is required since the precursors of most of these macromolecules are not amenable to surface-initiated polymerization. In this work, we report a versatile process for the simultaneous immobilization and cross-linking of a library of macromolecules on and into the blend membrane (PVDF-blend) of poly(vinylidene fluoride) and poly(methyl methacrylate)-co-poly(chloromethylstyrene). Sequential nucleophilic substitution reaction between activated halide moieties of the copolymer and amine groups of different macromolecules readily provided series of modified membranes. These membranes exhibited antifouling property superior to that of the unmodified membrane. The effectiveness of this technique has been demonstrated by the immobilization of pH or both pH- and temperature-responsive copolymer on PVDF-blend membrane for responsive separation of poly(ethylene oxide) and bovine serum albumin. Silver nanoparticles were also anchored on the select modified membranes surfaces for the enhancement of antibiofouling property. Our approach is useful to obtain verities of functional membranes and selection of membrane for a particular application.

Sustainable process for the preparation of potassium sulfate by electrodialysis and its concentration and purification by a nanofiltration process

A sustainable approach for the production of high purity potassium fertilizer (K2SO4) is highly needed to cope with the food crisis. High value K2SO4 produced by the conventional process as well as by metathesis electrodialysis (mED) contains precursor salts as impurities. With the increase of produced K2SO4 concentration, the amount of impurity in the product also increases. Hence, a suitable strategy is required for the rapid and effective production of high concentration and relatively pure K2SO4. Herein, we report a combination of electrodialysis and nanofiltration (NF) processes for the scalable production, purification and concentration of K2SO4. Several parameters such as applied voltage, ratio of the reactants (Na2SO4 and KCl) and their concentrations were optimized to obtain K2SO4 with relatively high concentration along with good purity via the mED process. The K2SO4 obtained by mED was further subjected to NF using a poly(piperazineamide) thin film composite NF membrane to concentrate and to eliminate the chloride (Cl−) and associated monovalent cations from the product stream. The NF parameters such as feed pH and applied pressure were adjusted to obtain a high concentration of aqueous K2SO4 with purity as high as ca. 99%. This process thus provides a suitable way for the production and recovery of solid K2SO4.

Anti-organic fouling and anti-biofouling poly(piperazineamide) thin film nanocomposite membranes for low pressure removal of heavy metal ions

Propensity towards anti-organic fouling, anti-biofouling property and low rejection of multivalent cation (monovalent counter ion) restricts the application of the state-of-art poly(piperazineamide) [poly(PIP)] thin film composite (TFC) nanofiltration (NF) membrane for the treatment of water containing toxic heavy metal ions, organic fouling agents and microbes. Herein, we report the preparation of thin film nanocomposite (TFNC) NF membranes with improved heavy metal ions rejection efficacy, anti-biofouling property, and anti-organic fouling properties compared to that of poly(PIP) TFC NF membrane. The TFNC NF membranes were prepared by the interfacial polymerization (IP) between PIP and trimesoyl chloride followed by post-treatment with polyethyleneimine (PEI) or PEI-polyethylene glycol conjugate and then immobilization of Ag NP. The IP was conducted on a polyethersulfone/poly(methyl methacrylate)-co-poly(vinyl pyrollidone)/silver nanoparticle (Ag NP) blend ultrafiltration membrane support. The TFNC membranes exhibited >99% rejection of Pb2+, 91-97% rejection of Cd2+, 90-96% rejection of Co2+ and 95-99% rejection of Cu2+ with permeate flux ∼40Lm-2h-1 at applied pressure 0.5MPa. The improved heavy metal ions rejection efficacy of the modified NF membranes is attributed to the development of positive surface charge as well as lowering of surface pore size compared to that of unmodified poly(PIP) TFC NF membrane.

Synthesis and Multi-Responsive Self-Assembly of Cationic Poly(caprolactone)-Poly(ethylene glycol) Multiblock Copolymers

Individual dissimilar blocks were combined to obtain well-defined An Bn and (A-B-A)n types of cationic amphiphilic multiblock copolymers (MBCs) through mild sequential nucleophilic substitution without formation of byproducts. MBCs were synthesized by reacting end-functional polymer blocks of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), and PCL-b-PEG-b-PCL. For selective degradation, acid- and base-labile ester as well as reducible disulfide groups were introduced as linkers between the blocks. The micellar self-assemblies of these MBCs showed exceptional stability under normal physiological conditions with negligible release of the guest molecules. Selective disassembly under mildly acidic and basic conditions or in the presence of reducing agents caused triggered release of the guest molecules. This strategy is versatile and opens an opportunity to obtain a variety of tailor-made MBCs for selective and triggered release of therapeutics.

Self-Assembly of Partially Alkylated Dextran-graft-poly[(2-dimethylamino)ethyl methacrylate] Copolymer Facilitating Hydrophobic/Hydrophilic Drug Delivery and Improving Conetwork Hydrogel Properties

Key issues of injectable hydrogels are incapability of loading hydrophobic drugs due to insolubility of drugs in aqueous prepolymer solution as well as in hydrogel matrix, and high water swelling, which leads to poor mechanical and bioadhesive properties. Herein, we report that self-assembly of partially long-chain alkylated dextran- graft-poly[(2-dimethylamino)ethyl methacrylate] copolymer in aqueous solution could encapsulate pyrene, a hydrophobic probe, griseofulvin, a hydrophobic antifungal drug, and ornidazole, a hydrophilic antibiotic. Addition of activated chloride terminated poly(ethylene glycol) (PEG) into the guest molecules loaded copolymer solution produced an injectable dextran- graft-poly[(2-dimethylamino)ethyl methacrylate]-linked-PEG conetwork hydrogel. The alkylated hydrogels exhibited zero order release kinetics and were mechanically tough (50-54 kPa storage modulus) and bioadhesive (8-9 kPa). The roles of alkyl chains and dextran on the drug loading-release behavior, degradation behavior, gelation time, and the mechanical property of the hydrogels have been studied in details. Additionally, DNA hybrid composite hydrogel was formed owing to the cationic nature of the prepolymer solution and the hydrogel. Controlled alkylation of a prepolymer thus highlights the potential to induce and enhance the hydrogel property.