Delivery Strategies for Nucleic Acids

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Utilization of nucleic acids to manipulate genetic information within a cell is known as gene therapy. It has provided researchers with unprecedented opportunities in treatment and mitigation of several life-threatening diseases. Gene therapy is an attractive alternative to conventional chemotherapy or radiation therapy due to its high efficiency, minimal side effects, and potential to evade drug resistance. The versatility of gene therapy makes it useful for the treatment of diseases dangerous disease like cancer. However, delivery of nucleic acid payloads to the intended target has been the bottleneck in clinical translation of such therapies. Here, we have developed and evaluated three different delivery systems (lipid based, polymer based and lipid-polymer hybrid) which can complex nucleic acid payloads, able to target specific cell types and get dissembled on cellular internalization to release the therapeutic payload. Our lipid and lipid-polymer hybrid delivery systems utilize a novel bacterial peptide sequence which enables these vectors to “stick” to fibronectin present in tumor extracellular matrix making them attractive for intravesical administration in bladder cancer management. Additionally, these systems have pH responsive modalities which aids in vector dissemble under acidic endosomal pH conditions for efficient release of therapeutic cargos after internalization into target cells.In our efforts to develop an ideal delivery system with a tunable the assembly/disassembly properties, we synthesized a library of pendent polymer with biodegradable polycarbonate backbone. The ability of the pendent groups to form host-gest interaction with hydrophobic core of cationic cyclodextrins determined the stability of the delivery system. We demonstrate the capability of such polymer systems to form nano-dimensinal complexes with nucleic acid and transfect cancer cells. The above-mentioned property of cyclodextrins to form host-guest interaction with hydrophobic molecules also forms the basis of its utilization in the treatment of a rare metabolic disorder called Niemann Pick type C disease where there the cells loses the ability to remove stored cholesterol from endo-lysosomal compartments. Cyclodextrin forms host-gest complexes with aberrantly stored cholesterol and helps normalization of cellular cholesterol level. However, the soluble nature and small size of the cyclodextrin causes very rapid clearance for the body necessitating dosage levels as high as 9000mg/kg for therapeutic benefit. We have also developed a library of polyrotaxanes, where multiple cyclodextrins are threaded onto linear polymer chains and end-capped with bulky groups to prevent slippage. This kind to assembly drastically increases the systemic circulation time by preventing rapid renal clearance. We evaluated the ability of these constructs to serve as a long circulation delivery system for delivery of β-cyclodextrins for potential treatment of Niemann Pick type C disease. Finally, we have studied the structure-function relationships of these supramolecular assemblies to aid in rational design of therapeutic polyrotaxanes.