(M1430-01-07) A Novel Octreotide Conjugated PEGylated Liposomal Paclitaxel for Targeted Pancreatic Cancer Treatment

Purpose: The somatostatin receptor 2 (SSTR2) abundantly overexpressed in pancreatic cancer cells represents an attractive target for the cancer-specific delivery of therapeutic agents. SSTR2 ligands can potentially be used for the targeted delivery of anticancer drugs. In this study, a liposomal drug delivery system (DDS) with paclitaxel (PTX) modified with a synthetic somatostatin (SST) analog, 5-pentynecarbonyl-octreotide (OCT), was developed and tested. The study is to understand targeting of therapeutics to pancreatic cancer by ligands to Somatostatin receptors, evaluate targeted liposomal delivery of paclitaxel and analyze the cytotoxicity and anticancer efficacy of the proposed delivery system.

Methods: Three types of human pancreatic cancer cells (PANC-1, MiaPaca-2 and CFPAC-1) with different expression of SSTR2 were used. The expression of SSTR2 genes and proteins were measured by RT-qPCR, Western blotting, immunocytochemistry and flow cytometry. Cellular uptake and cytotoxicity were analyzed by confocal microscope and MTT assay, respectively.

Results: All three types of evaluated cells overexpressed the SSTR2 gene and protein, and these expression in CFPAC-1 cells was 4.2 and 2.5-fold higher when compared with MiaPaca-2 and PANC-1 cells, respectively. Confocal microscope images showed that liposomes successfully internalized by pancreatic cancer cells and PTX was released in the cytoplasm and partially accumulated in the nuclei (Figure 1). Cellular penetration of PTX delivered by the targeted DDS was more pronounced when compared with non-targeted formulation and free drug in the same concentration. Cytotoxicity of targeted DDS containing PTX was substantially higher when compared with non-targeted system and correlated with the expression of the SSTR2 gene.

Conclusion: A chemically modified SST2 (5-pentynecarbonyl-octreotide) conjugated to PTX-loaded liposomes possessed high specificity to human pancreatic cancer cells overexpressed SSTR2, substantially enhanced the accumulation of the drug, significantly inhibited proliferation of these cells and demonstrated augmented cytotoxicity when compared with non-targeted system and free drug. Therefore, the proposed OCT-conjugated liposomal PTX can be considered as a promising anticancer formulation specific to pancreatic cancer cells with high expression of SSTR2.

Acknowledgements:The research was supported in part by R01 CA269513 grant.