PH/thermosensitive liposomes modified with poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for focused ultrasound-triggered release of Doxorubicin
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Chemotherapy requires the systemic administration of large doses of highly toxic antineoplastic agents in order to achieve therapeutically relevant concentrations at the tumor. These drugs typically act by impairing cell mitosis, effectively targeting rapidly-dividing cells that are the hallmarks of cancer. Non-cancerous cells that divide rapidly under normal circumstances are often damaged, leading to adverse side effects including myelosuppression, alopecia, and organ-specific toxicities. One potential means of reducing off-site toxicities is to encapsulate highly toxic chemotherapeutics into thermosensitive liposomes (TSL). These nanoscale structures are formed from temperature-sensitive lipids, and are designed to passively target the tumor by being large enough to avoid renal clearance while small enough to slip through leaky blood vessels characteristic of tumor vasculature. At the tumor, externally applied heating triggers a burst release of therapeutically relevant concentrations of drug. Current TSL formulations suffer from (i) approaches for heating that put healthy tissue surrounding the tumor at risk; (ii) lack of stability at physiological conditions (e.g. premature leakage of drug); and (iii) lack of noninvasive approaches for monitoring temperature elevation. This project presents a dual pH/thermosensitive liposome (PTSL) for the deliver of Doxorubicin (DOX), a commonly administered chemotherapeutic. Copolymers of temperature-responsive N-isopropylacrylamide (NIPAAm) and pH-responsive propylacrylic acid (PAA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, yielding copolymers with dual pH/temperaturedependent phase transition properties. When attached to liposomes, copolymers were membrane-disruptive m a pH/temperature-dependent manner, conferring pH/temperature-sensitive drug release properties to the liposome. These dual-sensitive properties can potentially exploit the slightly acidic environment of the tumor when PTSL are administered with externally applied heating. PTSL demonstrated enhanced release profile, significantly lower thermal dose threshold, and lower IC50 when compared to traditional TSL, and were stable in serum with minimal premature drug leakage. The application of MR-guided focused ultrasound (MRgFUS) as a noninvasive, highly controllable thermal source for triggering drug release and monitoring temperature elevations was demonstrated in vivo. PTSL combined with MRgFUS treatment resulted in delayed tumor growth when compared to PTSL alone and control treatments. This PTSL-MRgFUS delivery system thus addresses the limitations of existing TSL therapies and has potential applications in the clinic.
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