In vivo targeting of a tumor-antigen encoded DNA vaccine to dendritic cells in combination with tumor-selective chemotherapy eradicates established mouse melanoma.

Despite remarkable progress during the past decade, eradication of established tumors by targeted cancer therapy and cancer immunotherapy remains an uphill task. Herein, we report on a combination approach for eradicating established mouse melanoma. Our approach employs the use of tumor selective chemotherapy in combination with in vivo dendritic cell (DC) targeted DNA vaccination. Liposomes of a newly synthesized lipopeptide containing a previously reported tumor-targeting CGKRK-ligand covalently grafted in its polar head-group region were used for tumor selective delivery of cancer therapeutics. Liposomally co-loaded STAT3siRNA and WP1066 (a commercially available inhibitor of the JAK2/STAT3 pathway) were used as cancer therapeutics. In vivo targeting of a melanoma antigen (MART-1) encoded DNA vaccine (p-CMV-MART1) to dendritic cells was accomplished by complexing it with a previously reported mannose-receptor selective in vivo DC-targeting liposome. Liposomes of the CGKRK-lipopeptide containing encapsulated FITC-labeled siRNA, upon intravenous administration in B16F10 melanoma bearing mice, showed remarkably higher accumulation in tumors 24 h post i.v. treatment, compared to their degree of accumulation in other body tissues including the lungs, liver, kidneys, spleen and heart. Importantly, the findings in tumor growth inhibition studies revealed that only in vivo DC-targeted genetic immunization or only tumor-selective chemotherapy using the presently described systems failed to eradicate the established mouse melanoma. The presently described combination approach is expected to find future applications in combating various malignancies (with well-defined surface antigens).

Combating Established Mouse Glioblastoma through Nicotinylated-Liposomes-Mediated Targeted Chemotherapy in Combination with Dendritic-Cell-Based Genetic Immunization.

Accomplishing significantly enhanced overall survivability (OS) remains a formidable challenge in combating glioblastoma. The presence of the blood-brain barrier acts as the major biological barrier in delivering drugs to the brain. Herein, liposomal formulations of two novel nicotinylated amphiphiles are reported for targeting potent anticancer drugs to orthotopic mouse glioblastoma. It is shown that intravenous administration of the potent signal transducer and activator of transcription 3 (STAT3) inhibitor (WP-1066)-loaded liposomes of nicotinylated amphiphiles in combination with in vivo dendritic cell (DC)-targeted subcutaneous genetic immunization (using tyrosinase-related protein-2 encoded DNA vaccine) markedly enhances the OS of orthotopic glioblastoma-bearing mice (by >500% compared to the OS for the control group). Notably, the overall survival benefits in orthotopic-brain-tumor-bearing mice treated with only targeted chemotherapy or with only in vivo DC-targeted genetic immunization are found to be significantly less. The presently described simple approach avoids the need of isolation of any autologous immune cells. In summary, the preclinical findings described herein open the door for combating glioblastoma in humans through harnessing synergistic effects of targeted chemotherapy and in vivo DC-targeted genetic immunization.