Abstract 5527: Oral administration of a nano-enabled form of Met-Enkephalin peptide controls pancreatic cancer growth

Abstract

Abstract Introduction Peptides are a potential source of highly specific bioactive molecules useful for the treatment of various conditions, including cancer. Their wider application is limited by their poor oral bioavailability due to e.g. rapid degradation in the gut or in the blood. Unfavorable physical-chemical properties can further limit their applicability. For example, Met-enkephalin (MENK) is an endogenous opioid peptide having anti-tumor activity against a diverse range of cancers. While previous reports describe anti-cancer effects of MENK after parenteral administration in humans this approach has significant limitations because only low drug concentrations are achievable due to the peptide's poor aqueous solubility. Here, we demonstrate that a nano-enabled form of MENK created by combining MENK with the amphiphilic polymer GCPQ to form ‘molecular envelopes’, is orally bioavailable and active in murine models of pancreatic cancer. Method Nano-enabled MENK (10 mg/ml) formulation was prepared by encapsulating the peptide in GCPQ nanoparticles (50 mg/ml). A MENK solution was prepared in water (10 mg/ml). Swiss nude mice bearing tumor xenografts of pancreatic cancer cells (MIA PaCa-2) were randomized in to three groups (n = 5), each receiving MENK (50 mg/kg), nano-enabled MENK formulation (50 mg/kg) or water. All formulations were orally administered every two days over a period of 29 days once tumors were fully established. Throughout the study the tumor volumes were measured using calipers and the body weight of the mice monitored. Results For mice treated with the nano-enabled MENK formulation at a dose of 50 mg/kg, a complete suppression in the tumor growth was observed within two weeks of the start of treatment which continued while treatment continued and for two weeks after withdrawal of the treatment on 4th week. In contrast, no statistically significant delay in tumor growth was observed for mice treated with the MENK solution (50 mg/kg) compared with the untreated control. Overall the treatment was well tolerated as suggested by the limited impact of therapy on animal body weight. In vivo pharmacodynamics studies demonstrated significantly higher anti tumor efficacy for nano-enabled MENK formulation compared to free MENK in established MIA PaCa-2 tumor xenograft model. Conclusion The current study demonstrates that the MENK peptide when administered orally in the form of nano-enabled ‘molecular envelopes’ is able to control the growth of MIA PaCa-2 pancreatic tumour xenograft tumors over a period of four weeks. The above results suggest that a nano-enabled oral form of this endogenous peptide could have wider application in cancer therapy. Furthermore, it suggests that other peptides with anti-cancer activity could be utilized as oral peptide pill for cancer therapy. Citation Format: Preethi Marimuthu, Ijeoma F. Uchegbu, Andreas G. Schätzlein. Oral administration of a nano-enabled form of Met-Enkephalin peptide controls pancreatic cancer growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5527. doi:10.1158/1538-7445.AM2015-5527