Graduate Student, University of Massachusetts Amherst
Templated Self-Assembly of Covalent Polymer Network for Traceless Intracellular Protein Delivery
Protein therapeutics offer significant advantages over small molecule drugs due to their intrinsic specificity and low immunogenicity. Demanding physicochemical property and low bioavailability of protein drugs call for appropriate delivery vehicles with superior shielding of payload from denaturing environment. Herein, we report on a reversible protein conjugation strategy for effective shielding of the payload and functional cytosolic delivery thereof. Exploiting the redox-inducible self-immolative backbone structure of our newly designed polymer, the protein cargo is conjugated through its surface exposed lysine residues. This efficient “shrink-wrapping” strategy ultimately leads to ‘traceless’ release of the protein through thiol-disulfide reshuffling. Functional and reversible delivery of proteins with a wide range of molecular weight and charge distribution demonstrated the versatility of the strategy. Together, this new strategy provides a simple and robust delivery platform potentially applicable to a broad range of proteins and might help design the next generation therapeutics.
Abstract: Conjugation of biologically active proteins to polymeric materials is of great interest in the treatment of cancer and other diseases of protein deficiency. The conjugation of such biomacromolecules is challenging both due to their hydrophilicity and propensity to denature under non-native conditions. We describe a novel reactive self-assembly approach to "wrap" a protein with polymers, simultaneously protecting its delicate folded state and silencing its enzymatic activity. This approach has been demonstrated using caspase-3, an apoptosis-inducing protein, as the first case study. The protein-polymer conjugation is designed to be reversed under the native conditions for caspase-3, that is, the reducing environment found in the cytosol. The current strategy allowed release and recovery of up to 86% of caspase activity and nanogel-caspase-3 conjugates induced 70-80% apoptotic cell death shortly thereafter. This approach is widely generalizable and should be applicable to the intracellular delivery of a wide range of therapeutic proteins for treatment of complex and genetic diseases.
Pub.: 04 Sep '15, Pinned: 07 Jul '17
Abstract: Trafficking proteins inside cells is an emerging field with potential utility in basic cell biology and biological therapeutics. A robust and sustainable delivery strategy demands not only good protection of the cargo but also reversibility in conjugation and activity. We report a protein-templated polymer self-assembly strategy for forming a sheath around the proteins and then tracelessly releasing them in the cytosol. The versatility of the approach, demonstrated here, suggests that the strategy is compatible with a wide array of biologics.
Pub.: 14 Apr '17, Pinned: 07 Jul '17
Abstract: Drug delivery vehicles that release one or more drugs, e.g., an opioid antagonist and/or an opioid, in response to changes in the chemistry of body fluids, specifically in response to changes in the partial pressure of CO2 in the environment of the hydrogel are described. The drug delivery vehicles include hydrogels that swell or shrink in response to changes in the partial pressure of CO2 in their environment, thus regulating release of an entrapped drug.
Pub.: 18 Aug '11, Pinned: 07 Jul '17
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