Saadyah Averick

Grafting challenging monomers from proteins using aqueous ICAR ATRP under bio-relevant conditions

Aqueous initiators for continuous activator regeneration atom transfer radical polymerization (ICAR ATRP) was applied to graft well defined acrylamide, N,N-dimethylacrylamide and N-vinylimidazole homo and block copolymers from a model protein initiator (bovine serum albumin (BSA)) under bio-relevant conditions. Using N-vinylimidazole as a ligand catalytic biohybrid nanoparticles were prepared by loading palladium into a block copolymer of poly(N-vinylimidazole)-b-poly(oligo(ethylene oxide) acrylate) grafted from BSA. The protein–polymer biohybrid catalyst successfully catalyzes Suzuki–Miyaura couplings in aqueous media under aerobic conditions.

Synthesis of Reactive Polymers for Acrolein Capture Using AGET ATRP.

Acrolein is a toxic metabolite of the anticancer agent cyclophosphamide (CP). Current strategies to mitigate acrolein toxicity are insufficient, and in this brief article, we report the synthesis of well-defined low molecular weight block copolymers using activators generated by electron transfer atom transfer radical polymerization (AGET ATRP) capable of reacting with the cytotoxic small molecule acrolein. Acrolein reactivity was introduced into the block copolymers via incorporation of either (a) aminooxy or (b) sulfhydryl groups. The cytoprotective effect of the polymers was compared to sodium 2-sulfanylethanesulfonate (mesna) the current gold standard for protection from CP urotoxicity, and we found that the polymers bearing sulfhydryl moieties demonstrated superior cytoprotective activity.

Synthesis and biological evaluation of fentanyl acrylic derivatives

The synthesis of novel fentanyl acrylate derivatives via bromo-fentanyl using Heck coupling is described. The synthesis is concise and represents an efficient and useful method for functionalizing fentanyl for medicinal chemistry investigations. The agonistic and analgesic activities are evaluated by Mu opioid receptor activation and hot plate assays in mice.

Extended-release of opioids using fentanyl-based polymeric nanoparticles for enhanced pain management

Opioid receptor agonists form the backbone of pharmacological pain management. The use of these drugs through the current delivery routes poses significant health risks, including abuse, addiction, respiratory depression, and death. Those risks can be alleviated through controlled release of opioids at therapeutic levels for prolonged periods. Biodegradable polymeric nanoparticles (NPs) have been utilized as controlled drug delivery vehicles due to their unique ability of presenting different molecules of interest at their surfaces. In this study, we focus on extended-release of the synthetic opioid fentanyl analogs for improved pain management. To this end, we report the formulation of fentanyl-bearing polylactide and polyglicolide NPs (Fen-PLA/PLGA NPs) with controlled size, surface features, and antinociceptive properties. Biocompatible Fen-PLA/PLGA NPs were formulated through opioid initiators Fen-OH and Fen-Ary-EtOH, to prepare opioid chain-end functional biodegradable polymers. The results demonstrate that a single subcutaneous dose of the prepared NPs delivers therapeutically relevant doses for up to six days in a mouse model of acute nociception without unwanted burst-release. To further our aim of precise administration of the novel opioid delivery systems into skin tissue, we envisioned and fabricated dissolvable microneedle arrays (MNAs) that integrate the formulated NPs at their tips. Our novel biohybrids, which can be delivered precisely and minimally-invasively using dissolvable MNAs, may be utilized to formulate opioids towards preventing overdose and abuse.

Grafting-from lipase: utilization of a common amino acid residue as a new grafting site

Protein–polymer hybrids are used in a variety of fields including catalysis, detection, and therapeutics. The grafting-from method for the synthesis of these biohybrids has gained popularity due to the ease of synthesis and purification. In this method, an initiator or chain transfer agent (CTA) is ligated onto an amino acid residue, typically lysine or cysteine, and polymers are subsequently grown in situ. In this manuscript, we report the preparation of protein polymer hybrids by grafting-from a previously overlooked acidic amino acid residue (glutamic and aspartic acid) and compare our results to protein polymer hybrids, grafted from the traditional lysine residue. Herein, we conjugated an atom transfer radical polymerization (ATRP) initiator to acidic amino acid residues and lysine residues and grew polymers from Thermomyces lanuginosa lipase (TL). N-[3-(N,N-Dimethylamino)propyl] acrylamide was grafted from the TL initiator, and the enzymatic activity of protein polymer hybrids was compared. We found that the acidic residues are easily modified with multiple ATRP initiators and polymers are readily grown. Additionally, the hybrids grafted from acidic residues demonstrated a 50% increase in enzyme activity compared to those grafted from lysine residues. Moreover, the activity was higher than that of native lipase TL in both cases. The polymers that were grafted-from the acid residues tended to provide the hybrids with a higher activity at elevated temperatures. These results point to a new amino acid ligation strategy for preparing protein polymer hybrids via a grafting-from method.