Abstract 304: Effect of paclitaxel stereochemistry on x-ray-triggered release of paclitaxel from CaWO4/paclitaxel-coloaded PEG-PLA nanoparticles

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the 8th most common cancer in the United States predominantly affecting people over 65 years of age with an increasing rate of incidence across the world. Current therapies for HNSCC include surgical resection, chemotherapy (CT), and radiotherapy (RT). For locally advanced/unresectable HNSCC, the CT-RT combination (“chemoradiation”) has been shown to be more effective than CT or RT alone, and is currently the standard of care. Intratumoral (IT) chemotherapy-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT that severely affects a patient’s quality of life. For realization of maximum benefits from IT CT-RT, our team has developed a radiation-controlled drug release nanoparticle formulation (paclitaxel (PTX) and CaWO4 nanoparticles (CWO NPs) co-encapsulated within a capsule formed by poly(ethylene glycol)-poly (lactic acid) (PEG-PLA), named “PEG-PLA/CWO/PTX NPs”). This unique formulation releases PTX only when it is exposed to X-ray irradiation. We have previously reported that IT-administered PEG-PLA/CWO/PTX NPs stay within the tumor for at least a month, producing significant therapeutic effects in terms of tumor suppression and survival in mouse models of HNSCC. This work demonstrates the effect of PTX stereochemistry on radiation-controlled release of the drug from a nano polymer matrix system (PEG-PLA/CWO/PTX NPs). The stereoisomertic characteristics of PTX products from two different manufacturers (“PTX-S”, and “PTX-B”) were analyzed by Raman spectroscopy, circular dichroism and 2D HMQC/NOESY NMR measurements. In their unencapsulated (free) state, PTX-S and PTX-B were comparable in their ability to kill cancer cells in vitro. However, they were found to be significantly different in water solubility; PTX-S (water solubility ≈ 4.69 μg/mL) is about 19 times more water soluble than PTX-B (water solubility ≈ 0.25 μg/mL). This difference in water solubility was found to cause a large difference in X-ray-triggered release kinetics of the PTX loaded within the PEG-PLA/CWO/PTX NPs in both in vitro and in vivo environments; PTX-S is released from PEG-PLA/CWO NPs significantly faster upon X-ray irradiation than PTX-B. This difference in release kinetics produced an interesting difference in their time-dependent therapeutic effects; at short times (< 1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor suppression effect; on the other hand, PEG-PLA/CWO/PTX-B NPs had a longer lasting radio-sensitizing effect. In summary, the stereoisomers of PTX exhibit significantly different PK characteristics when used with controlled release carriers, even though they are pharmacologically indistinguishable in their unformulated form. Citation Format: Kaustabh Sarkar, Sandra Torresgrossa-Allen, Mark P. Langer, Gregory Durm, Sanjeev Narayanan, Bennett D. Elzey, You-Yeon Won. Effect of paclitaxel stereochemistry on x-ray-triggered release of paclitaxel from CaWO4/paclitaxel-coloaded PEG-PLA nanoparticles [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 304.