Abstract 3624: Improved intratumor drug delivery and therapeutic efficacy in pancreatic cancer by albumin-Cisplatin complex

Abstract

Abstract Background: The tumor microenvironment in pancreatic cancer is widely known for its abundant stroma and lacking of tumor blood vessels. Many effective therapeutic agents evaluated in vitro failed to show any benefits in vivo due to the inefficient drug delivery into the tumors. Albumin was reported to naturally accumulate in several types of solid tumors including sarcomas, lung cancer, etc. In this study, we systematically investigated the tumor accumulation and penetration of albumin in pancreatic cancer, and evaluated whether albumin could improve the intratumor drug delivery and therapeutic efficacy by albumin-drug complex. Methods: We prepared a red fluorescence dye (6-TMR)-labeled albumin and studied the tumor accumulation and penetration of albumin in both orthotopic xenograft and the genetically engineered KPC mouse model by in vivo fluorescence imaging and confocal microscope. To further investigate the drug delivery capacity of albumin in pancreatic cancer, we used Cisplatin as a model drug and prepared albumin-Cisplatin complex. Organ and intratumor drug distribution of Cisplatin were measured by ICP-MS and LA-ICP-MS imaging, respectively. Results: Albumin-6-TMR showed tumor-selective accumulation in both orthotopic xenograft and KPC tumors, with about 50-fold higher radiant efficiency than that of free 6-TMR in KPC tumors at 12 h. Intriguingly, the confocal results indicated that albumin-6-TMR could penetrate into the interior of tumor tissues and stay for at least 72 h while no obvious fluorescence was seen in free 6-TMR group. The mechanism of albumin accumulation and penetration in pancreatic tumors is still under investigation. Moreover, administration of albumin-Cisplatin complex significantly reduced Vd by nearly 25 times and increased AUC of Cisplatin in plasma by 33 times, and improved the MRT and AUC of Cisplatin in orthotopic xenograft tumors by 10 and 29 times, respectively. The LA-ICP-MS imaging was being used to confirm intratumor penetration and distribution of Cisplatin in KPC tumors. Finally, albumin-Cisplatin complex exhibited reduced systemic toxicity (the maximum tolerated dose was more than 60 mg/kg of Cisplatin, i.v.) and enhanced inhibition of tumor growth in subcutaneous PANC-1 xenograft mouse models. Importantly, albumin-Cisplatin complex prolonged the survival of orthotopic MIA PaCa-2 xenograft mouse models compared with free Cisplatin. Conclusion: In summary, we have shown for the first time that albumin as a drug carrier could improve intratumor drug delivery in both orthotopic xenograft and KPC tumors. And albumin-Cisplatin complex could significantly reduce systemic toxicity and improve therapeutic efficacy of Cisplatin in preclinical pancreatic cancer models. Together, albumin can be a promising drug carrier and provides a new insight into anti-cancer drug delivery in pancreatic cancer. Citation Format: Chao Kong, Junxiao Ye, Zhengsheng Liu, Weijian Kong, Mengnan Sun, Huiqin Liu, Fang Yuan, Feng Qian. Improved intratumor drug delivery and therapeutic efficacy in pancreatic cancer by albumin-Cisplatin complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3624.