Co-Delivery of Peptide QK and WKYMVm for Minimally Invasive Therapeutic Angiogenesis in Treating Critical Limb Ischemia

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Pang, Yuan
Drug Delivery , Therapeutic Angiogenesis , Biomaterials , Critical Limb Ischemia , Biodegradable Polymers
Critical Limb Ischemia (CLI) is a leading cause of mortality among vascular diseases. Current surgical treatments often fail due to the ineffective restoration of blood flow in the diseased vasculature, leading to high rates of amputation and mortality. The delivery of therapeutic peptides emerges as a promising alternative, offering the potential to stimulate non-invasive angiogenesis at ischemic sites. However, current delivery platforms still face challenges such as burst release, incomplete delivery, and the potential to generate acidic by-products that deactivate the therapeutics. To address these issues, we propose a manually injectable viscous liquid platform consisting of an aliphatic polycarbonate for the delivery of pro-angiogenic peptides QK and WKYMVm. The polymer bears pendant short-chain fatty acids (SCFAs) that have the potential to polarize M2 macrophages and modulate the immune response. The system is also degradable into non-acidic products through intramolecular cyclization. In this work, we investigated the hydrolytic degradation of copolymers composed of 5-hydroxyl trimethylene carbonate (HT) and 5-butyrate-trimethylene carbonate (BtT), as well as terpolymers containing trimethylene carbonate (T), HT, and BtT or 5-propionate-trimethylene carbonate (PtT), initiated with either 1-octanol or triethylene carbonate (EG3). The terpolymer system achieved a sustained degradation profile with maximum mass loss of 70% in four weeks. An HT content below 75% resulted in incomplete mass loss, as the HT units led to insufficient segmentation into water-insoluble oligomers. Terpolymers initiated with EG3 exhibited a higher degree of mass loss than those initiated with 1-octanol, due to increased chain flexibility, hydrophilicity, and solubility of cleaved oligomers when attached to EG3. The polymer degradation products were non-cytotoxic to 3T3 fibroblasts. Injectable peptide formulations with single or dual loading of QK and WKYMVm were successfully created, achieving sustained release of structurally intact WKYMVm and QK over four weeks, with near-complete release of WKYMVm and 71% of QK. Additionally, we investigated the feasibility of creating solid delivery devices by incorporating UPy motifs into the originally amorphous T-based polymer, enabling a semi-crystalline transition through terminal dimerization induced by quadruple hydrogen bonds.
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