Abstract 2166: Targeted delivery of chemotherapeutic agents to solid tumors via systemic Nano-diamino-tetrac

Abstract

Abstract Covalently bound to a poly (lactic-co-glycolic acid) (PLGA) polymer via a linker, tetraiodothyroacetic acid (tetrac) as Nano-diamino-tetrac (NDAT) targets a specific cell surface receptor on the extracellular domain of integrin αvβ3. The integrin is primarily expressed by cancer cells and rapidly dividing endothelial cells. The conjugation of tetrac and linker to a 120 nm PLGA nanoparticles prohibits cell entry of NDAT and offers an opportunity to load the nanoparticle with a generic cancer chemotherapeutic agent for cancer-targeted delivery. Even without a payload, NDAT has anticancer and anti-angiogenesis properties. For the current studies, xenografts of human urinary bladder cancer (263JBV) cells and of human pancreatic cancer (SUIT-2) cells were established in the nude mouse. Tumor growth and tumor content of cisplatin (263JBV xenografts) and of paclitaxel (SUIT-2 xenografts) were compared in the following animal cohorts: 1) untreated controls; 2) controls treated with void PLGA nanoparticles (NPs), 3) daily treatment with chemotherapeutic agent (cisplatin, 1 mg/kg, or paclitaxel, 0.3 mg/kg), alone, 4) daily treatment with sub-maximal NDAT, alone (0.3 mg tetrac equivalent/kg), 5) daily treatment with chemotherapeutic agent encapsulated into PLGA NPs (no tetrac), and 6) daily treatment with chemotherapeutic agent loaded into NDAT. NDAT dose in group 5 was 0.3 mg tetrac/kg. Daily drug treatments were continued for 3 weeks after establishment of xenografts. Urinary bladder tumor weight at animal sacrifice decreased insignificantly vs. controls in animals that received cisplatin or cisplatin + PLGA. Submaximal dosing of NDAT, alone, induced a small, but significant, decreased in tumor weight. Tumors in animals treated with NDAT bearing a payload of cisplatin decreased in weight by 50% (P <0.01) and mean cisplatin content (LC/MS/MS) of tumors (ng/gm of tissue) was 5-fold more than in animals treated with cisplatin, alone, and 3-fold more than in animals treated with PLGA NPs with encapsulated cisplatin. Animals receiving cisplatin, alone, developed neurotoxicity (inability to use the hind limbs). In pancreatic cancer xenografts, paclitaxel encapsulated into PLGA NPs, NDAT, alone, and NDAT bearing a payload of paclitaxel caused significant decreases in tumor weight. The greatest reduction in tumor weight (60%, P<0.01) was in animals exposed to NDAT bearing a drug payload and mean concentration of paclitaxel in these tumors (ng/gm tissue) exposed to an NDAT/paclitaxel payload was 5-fold more than in xenografts exposed to paclitaxel, alone, or paclitaxel encapsulated into PLGA NPs. Thus, the payload capacity of NDAT for cancer chemotherapeutic agents and tumor-specific delivery of cancer chemotherapeutic agents significantly increased bladder and pancreatic cancer content of, respectively, cisplatin and paclitaxel. Enhanced tumor size reduction and deceased systemic toxicity were achieved with this targeted approach. Citation Format: Thangirala Sudha, Dhruba J. Bharali, Noureldien HE Darwish, Melis Debreli-Coskun, Qishan Lin, Paul J. Davis, Shaker A. Mousa. Targeted delivery of chemotherapeutic agents to solid tumors via systemic Nano-diamino-tetrac. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2166.