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Therapeutic strategies for Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, remain challenging with poor prognosis, high mutational rate, and lowest patient survival among other cancers. The treatment options for managing PDAC are limited to surgery, radiation, and chemotherapy. However, surgery is the only treatment option that can cure the disease in about twenty percent of cases. Thus, Gemcitabine (GEM) remains the first-line drug in the clinic for PDAC treatment despite suboptimal clinical effects. These are primarily due to weak drug delivery and the development of chemoresistance resulting from mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic cages. Several new therapeutic approaches, including nanoparticle-based drug delivery procedures, are currently being investigated. In this study, we designed a pH-responsive PEG-b-poly (carbonate) block copolymer encapsulated ERK inhibitor (SCH772984) nanoparticles surface functionalized with tumor-penetrating peptide, iRGD to specifically target PDAC tumor tissue. By utilizing the ERKi-encapsulated pH-responsive targeted nanoparticles, we performed a combinational drug treatment of GEM and ERKi. We found that the pH-responsive targeted nanocarrier efficiently released ERKi in the hypoxic environment. The free GEM, combined with nanoencapsulated ERKi, demonstrated significant synergistic outcomes in vitro colony forming ability, migration, and motility in pancreatic cancer cell line MiaPaCa2. Moreover, combination therapy significantly enhanced the GEM effect in reducing PDAC growth in KPC mice and increasing the survival of the mice. Thus, our studies indicate that pH-responsive targeted nanocarrier-based delivery of ERKi in the hypoxic area of PDAC enhances the efficacy of GEM in PDAC. Citation Format: Debasmita Dutta, Archana De, Raj Shankar Hazra, Pratyusha Ghosh, Mohiuddin Quadir, Snigdha Banerjee, Sushanta K. Banerjee. pH-responsive targeted-nanoparticle releases encapsulated ERK-inhibitor effectively in the hypoxic microenvironment and sensitizes gemcitabine in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2701. |
