Tumor-targeting nanocomplex delivery of novel tumor suppressor RB94 chemosensitizes bladder carcinoma cells in vitro and in vivo

Purpose: RB94, a truncated form of RB110, has enhanced tumor suppressor potency and activity against all tumor types tested to date including bladder carcinoma. However, efficient, systemic delivery of the gene encoding RB94 specifically to tumors, is an obstacle to clinical application as an anticancer therapeutic. We have developed a systemically given, nanosized liposome DNA delivery system that specifically targets primary and metastatic disease.The ability of RB94, delivered via this nanocomplex, to sensitize bladder carcinoma to chemotherapy in vitro and in vivo was assessed. Experimental Design: The nanocomplex is an RB94 plasmid encapsulated by a cationic liposome, the surface of which is decorated with a tumor-targeting moiety, either transferrin (Tf/Lip/RB94) or an antitransferrin receptor single-chain antibody fragment (TfRScFv/Lip/ RB94). The ability of the complex to sensitize human bladder carcinoma HTB-9 cells to chemotherapeutics was assessed in vitro by XTTassay. In vivo tumor specificity and efficacy were tested in mice carrying HTB-9 tumors by PCR and tumor growth inhibition, respectively. Results: Transfection withTf/Lip/RB94 significantly sensitized HTB-9 cells to chemotherapeutic agents in vitro. Tumor specificity of the complex was shown in an orthotopic bladder tumor model by immunohistochemistry and PCR. Moreover, in mice bearing subcutaneous HTB-9 tumors, the combination of systemically given Tf/Lip/RB94 orTfRScFv/Lip/RB94 plus gemcitabine resulted in significant (P < 0.0005) tumor growth inhibition/regression and induction of apoptosis. Conclusions: Use of our tumor-targeting nanocomplex to specifically deliver the potent tumor suppressor RB94 efficiently to tumors has potential as a more effective treatment modality for genitourinary and other cancers.