Comparing influences of active targeting and nanoparticle size on tumor specificity in pancreatic adenocarcinoma

Abstract Purpose: While nanoparticles are widely studied as potential theranostic treatments for cancer, weak tumor specificity has hindered clinical translation. Features that contribute to tumor specificity are historically controversial, particularly when using clinically relevant models. Aggressive cancers, such as pancreatic ductal adenocarcinoma (PDAC), stand to benefit from development of highly specific nanoparticles as a theranostic drug delivery system. This work evaluates active targeting and nanoparticle size, in a silica-based nanoparticle for specific accumulation and release of contrast agent within an orthotopically implanted tumor. Methods: Mesoporous silica nanoparticles (MSNs) were synthesized with wormhole-like pores using a silica precursor to coat a surfactant scaffold. Chitosan was attached to MSN surface as a pH-responsive gatekeeper for encapsulated agents. A series of acidification and basification procedures resulted in loading of photoacoustic contrast agent IR780 within MSN pores. MSNs were further functionalized for attachment of V7 peptide to target aggressive and acidic pancreatic cancer. pH-sensitivity and tumor specificity/uptake was validated using an in vitro PDAC cell model (S2VP10L) prior to implantation and assessment in an animal model. Functionalized MSNs were intravenously injected into athymic mice with orthotopically implanted PDAC tumors. Near infrared fluorescence and optoacoustic imaging were used to evaluate the biodistribution of MSNs subsequent to treatment. Results: Zeta potential, DLS, and TEM were utilized to show three differently sized MSNs of 26, 45, and 73 nm and confirm conjugation of chitosan and V7 peptide. Dye-release assays indicated significantly increased agent release from MSNs in acidic pH (~90%) compared to biological pH (~15%) (p=0.001). Treatment of PDAC cell line with MSNs showed highest uptake and specificity with actively targeted 26nm particles and that all actively targeted MSNs exhibited greater specificity than all passively targeted MSNs (p<0.05). In vivo results utilizing optoacoustic imaging confirmed that active targeting produces a stronger tumor specificity, and that nanoparticle size has a secondary influence in which the smaller, 26 nm MSNs, showed optimal specificity (p<0.001). Ex vivo evaluation of organs was in agreement with in vivo observations. Conclusion: Active targeting outperforms nanoparticle size for facilitation of tumor-specific uptake in an acidic PDAC murine model. Active targeting was necessary for high accumulation of MSNs and contrast agent in the tumor. Nanoparticle size had a secondary, but notable influence on tumor uptake in which smaller sized MSNs resulted in higher tumor specificity. Citation Format: William M. MacCuaig, Abhilash Samykutty, Molly McNally, Ajay Jain, William E. Grizzle, Lacey R. McNally. Comparing influences of active targeting and nanoparticle size on tumor specificity in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2458.