The goal of this proposal is to investigate the feasibility of treating ovarian epithelial carcinoma (OEC) with intelligent virus-mimetic nanogels (VM-nanogels). The VM nanogel has a core-shell type micelle-like structure. The core is constructed with pH-sensitive polymer blocks and loaded with anticancer drugs such as doxorubicin (DOX) and paclitaxel (PTX). The hydrophilic poly(ethylene glycol) (PEG) shell of the VM-nanogel is partially cross-linked with macomolecules, such as albumin, to sustain its structural integrity. The surface is further modified with a cell penetrating peptide (such as TAT in this proposal) for active cell entry, yielding VM(TAT)-nanogel. The surface TAT of VM(TAT)-nanogel is then effectively shielded in the vascular space (pH 7.4) by counter ionic polymers, such as PEG-b-polysulfonamide, which will minimize interactions with normal healthy tissues but expose the tumor cells/tissue by deshielding within the tumor's extracellular pH. Preliminary results demonstrate that DOX-loaded VM(F)-nanogels, conjugated with folate (F), are highly cytotoxic to both sensitive and multidrug resistant (MDR) cancer cells and migration/reentry into neighboring intact cancer cells. Major functions documented were: 1) folate receptor mediated endocytosis, 2) triggered release of DOX by endosomal pH, 3) endosomal membrane disruption by the volume transition/osmotic pressure of VM(F)-nanogels, 4) minimal release of DOX in the cytosol, and 5) escape from dead cancer cells and re-entry into neighboring cells. The VM(F)-nanogels are eventually disintegrated and eliminated. The preliminary results also demonstrate the feasibility of a tumor pH-specific deshielding mechanism for TAT. This unique approach will maximize therapeutic effects with minimal amounts of a selected drug and carrier materials and is expected to overcome drug resistance. The VM(TAT) nanogel will avoid concerns of micelle stability in biological systems and the heterogeneity issue of cell surface markers including folate receptor in the clinical setting.
Four specific aims to achieve the stated goal are outlined in this application.
Despite clinical advances attributed to cytoreductive surgery and combination chemotherapy, we have failed to significantly increase the survival rate for patients diagnosed with epithelial ovarian cancer over the last three decades. Our long-term goal is to develop a new generation polymeric nano-carrier system with a virus-like re-entry function through translational studies, ultimately resulting in a more effective and less toxic treatment leading to increased survival rates for all the women suffering from ovarian cancer.
