MUCUS-PENETRATING NANOCARRIERS FOR CANCER THERAPY AND IMAGING

Nanocarrier-based treatment allows preferential delivery of therapeutics and/or imaging contrast agents to tumors, and has been found to improve efficacy, reduce side effects, and enhance diagnosis and monitoring of cancer treatment. One strategy to target tumors localized at tissue surfaces, such as the mucosae covering the respiratory, gastrointestinal, and female reproductive tracts, is to deliver therapeutics via nanocarriers directly to the local diseased tissues. However, nanocarriers must efficiently bypass multiple biological barriers, especially the viscoelastic mucus linings that rapidly remove foreign particles from mucosal surfaces, to reach the underlying tumor tissues. In this dissertation, I developed three formulations of nanocarriers that can effectively penetrate the mucus barrier for local chemotherapy on mucosal surfaces. These three “mucus-penetrating particles” (MPP) formulations are based on (i) biodegradable polymeric nanocarriers, (ii) pure-drug based nanosuspensions, and (iii) liposomes, respectively. The surface of each MPP formulation was modified, either covalently or non-covalently, with a dense layer of low molecular weight polyethylene glycol (PEG) that functions as the muco-inert shielding. All MPP formulations demonstrated rapid movement in human mucus samples at speeds only ~10-fold lower than their theoretical speeds in water, and >100-fold faster than the uncoated, mucoadhesive conventional particles (CP). In vivo experiments further demonstrated the therapeutic advantages of these MPP formulations over CP, including more uniform distribution and prolonged retention on mucosal tissues. Each formulation also features its unique encapsulation capacity and release kinetics of hydrophobic and/or hydrophilic payloads. In the orthotopic TC-1 mouse cervical tumor model, it was demonstrated that paclitaxel (PTX)-loaded biodegradable MPP suppressed tumor growth more effectively and prolonged median survival of mice compared to free PTX or PTX-loaded CP. Taking advantages of diamagnetic chemical exchange saturation transfer magnetic resonance imaging (diaCEST MRI), I further developed MRI-traceable liposomal MPP loaded with barbituric acid, a biocompatible diaCEST contrast agent. Using diaCEST MRI, it was demonstrated in mice that liposomal MPP provided uniform mucosal coverage post intravaginal administration, and that similarly engineered diaCEST liposomes enriched in tumors post intravenous administration. These results substantiated the strong potential of MPP for treatment and imaging of tumors localized to mucosal surfaces, such as early stage cervical cancer