Fabrication of poly(ß-amino ester) and hyaluronic acid based pH responsive nanocomplex as an antibiotic release system.

World Health Organization (WHO) warns about antimicrobial resistance (AMR) considered as the most serious threats to global health, food security, and development. There are various efforts for elimination of this serious issue. These efforts include education of individuals, new policies, development of new antimicrobials and new materials for effective delivery. Novel drug delivery systems with ability of local and on-demand delivery are one of the promising approaches for prevention of AMR. In this regard, a pH-responsive antibiotic delivery system based on pH-responsive poly(ß-amino ester) (PBAE) and enzyme responsive hyaluronic acid (HA). The polymeric nanocomplexes were obtained via electrostatic complexation of PBAE and HA in the presence of a model antibiotics, colistin and vancomycin. The particle sizes at pH 7.4 were determined in the range of 131-730 nm and 120-400 nm by DLS and STEM, respectively. When pH was switched from 7.4 to 5.5, the hydrodynamic diameter increased 2.5-32 fold. The drug release performances were tested using FITC-labeled antibiotics via fluorescence spectroscopy. The nanocomplexes released the drugs more at pH 5.5 compared to pH 7.4. Antibacterial activity of the system was evaluated on various bacteria. The nanocomplex loaded with the antibiotics exhibited significantly greater efficacy against E. coli and S. aureus.

Glycopolymer and Poly(ß-amino ester)-Based Amphiphilic Block Copolymer as a Drug Carrier.

Glycopolymers are synthetic macromolecules having pendant sugar moieties and widely utilized to target cancer cells. They are usually considered as a hydrophilic segment of amphiphilic block copolymers to fabricate micelles as drug carriers. A novel amphiphilic block copolymer, namely, poly(2-deoxy-2-methacrylamido-d-glucose-co-2-hydroxyethyl methacrylate)-b-poly(ß-amino ester) [P(MAG-co-HEMA)-b-PBAE], with active cancer cell targeting potential and pH responsivity was prepared. Tetrazine end functional P(MAG-co-HEMA) and norbornene end functional PBAE blocks were separately synthesized through reversible addition fragmentation chain transfer polymerization and Michael addition-based poly-condensation, respectively, and followed by end-group transformation. Then, inverse electron demand Diels Alder reaction between the tetrazine and the norbornene groups was performed by simply mixing to obtain the amphiphilic block copolymer. After characterization of the block copolymer in terms of chemical structure, pH responsivity, and drug loading/releasing, pH-responsive micelles were obtained with or without doxorubicin (DOX), a model anticancer drug. The micelles exhibited a sharp protonated/deprotonated transition on tertiary amine groups around pH 6.75 and the pH-specific release of DOX below this value. Eventually, the drug delivery potential was evaluated by cytotoxicity assays on both the noncancerous human umbilical vein endothelial cell (HUVEC) cell line and glioblastoma cell line, U87-MG. While the DOX-loaded polymeric micelles were not toxic in noncancerous HUVEC cells, being toxic only to the cancer cells indicates that it is a potential specific cell targeting strategy in the treatment of cancer.

Homodimeric Protein-Polymer Conjugates via the Tetrazine-trans-Cyclooctene Ligation.

Tetrazine end-functionalized telechelic polymers were synthesized by controlled radical polymerization (CRP) and employed to generate T4 Lysozyme homodimers. Mutant T4 Lysozyme (V131C), containing a single surface-exposed cysteine, was modified with a protein-reactive trans-cyclooctene (T4L-TCO). Reversible addition-fragmentation chain transfer (RAFT) polymerization yielded poly(N-isopropylacrylamide) (pNIPAAm) with a number average molecular weight (Mn by 1H-NMR) of 2.0 kDa and a dispersity (D by GPC) of 1.05. pNIPAAm was then modified at both ends by post-polymerization with 6-methyl tetrazine. For comparison, 2.0 kDa bis-tetrazine poly(ethylene glycol) (PEG) and 2.0 kDa bis-maleimide pNIPAAm were synthesized. Ligation of T4L-TCO to bis-tetrazine pNIPAAm or bis-tetrazine PEG resulted in protein homodimer in 38% yield and 37% yield, respectively, after only 1 hour, whereas bis-maleimide pNIPAAm resulted in only 5% yield of dimer after 24 h. This work illustrates the advantage of employing tetrazine ligation over maleimide thiol-ene chemistry for the synthesis of protein homodimer conjugates.

A simple route to synthesis of branched and cross-linked polymers with clickable moieties by photopolymerization.

Lightly branched, hyperbranched and cross-linked polymers with clickable sites were synthesized via a modified version of self-condensing photoinitiated copolymerization of methyl acrylate (MA) with propargyl acrylate (PA). The method is based on the use of a PA monomer containing two polymerizable groups, namely acrylate and propargyl groups with different reactivities in photoinitiated free radical copolymerization with MA.

Synthesis of block copolymers by combination of atom transfer radical polymerization and visible light-induced free radical promoted cationic polymerization.

A new synthetic approach for the preparation of block copolymers by mechanistic transformation from atom transfer radical polymerization (ATRP) to visible light-induced free radical promoted cationic polymerization is described. A series of halide end-functionalized polystyrenes with different molecular weights synthesized by ATRP were utilized as macro-coinitiators in dimanganese decacarbonyl [Mn(2) (CO)(10) ] mediated free radical promoted cationic photopolymerization of cyclohexene oxide or isobutyl vinyl ether. Precursor polymers and corresponding block copolymers were characterized by spectral, chromatographic, and thermal analyses.

A one pot, one step method for the preparation of clickable hydrogels by photoinitiated polymerization.

Current preparation methods for hydrogels based on redox or photopolymerization of water soluble monomers are simple to use, and flexible, but have the drawback of requiring additional modification steps for tuning or introducing properties for specific purposes. We have devised a simple and rapid synthetic strategy to prepare hydrogels possessing reactive sites to incorporate any molecules of interest by "Click Chemistry". The strategy is based on the use of propargyl acrylamide (PAm) as comonomer together with acrylamide (AAm) and N,N'-methylene bisacrylamide (BAAm) as crosslinker in photoinitiated polymerization. With the selective reactivity of photochemically generated free radicals towards acrylic function of PAm, hydrogels with clickable acetylene groups can be prepared in one pot, one step manner. Based on the acetylene functionality, any molecule possessing azide groups can be conjugated onto hydrogel by "Click Chemistry" as demonstrated on the example of fluoroscent azide functional pyrene.

In situ synthesis of biomolecule encapsulated gold-cross-linked poly(ethylene glycol) nanocomposite as biosensing platform: a model study.

In situ synthesis of poly(ethylene glycol) (PEG) hydrogels containing gold nanoparticles (AuNPs) and glucose oxidase (GOx) enzyme by photo-induced electron transfer process was reported here and applied in electrochemical glucose biosensing as the model system. Newly designed bionanocomposite matrix by simple one-step fabrication offered a good contact between the active site of the enzyme and AuNPs inside the network that caused the promotion in the electron transfer properties that was evidenced by cyclic voltammetry as well as higher amperometric biosensing responses in comparing with response signals obtained from the matrix without AuNPs. As well as some parameters important in the optimization studies such as optimum pH, enzyme loading and AuNP amount, the analytical characteristics of the biosensor (AuNP/GOx) were examined by the monitoring of chronoamperometric response due to the oxygen consumption through the enzymatic reaction at -0.7 V under optimized conditions at sodium acetate buffer (50 mM, pH 4.0) and the linear graph was obtained in the range of 0.1-1.0 mM glucose. The detection limit (LOD) of the biosensor was calculated as 0.06 mM by using the signal to noise ratio of 3. Moreover, the presence of AuNPs was visualized by TEM. Finally, the biosensor was applied for glucose analysis for some beverages and obtained data were compared with HPLC as the reference method to test the possible matrix effect due to the nature of the samples.