Preclinical Investigation of Hsp27 LNA as a Novel Radiosensitizer in Head-and-Neck Cancer

Abstract

chemoradiation therapy regimens, cisplatin is one of the most commonly utilized agents. Although cisplatin is highly effective as a radiosensitizer, its use has been limited by toxicity. Therefore, one of the goals of radiation oncology research has been identifying methods to improve cisplatin’s efficacy while lowering its toxicity. While traditional drug delivery strategies such as intra-arterial delivery have failed, the development of nanoparticle (NP) drug delivery vehicles offers an unprecedented opportunity. NPs are known to preferentially accumulate in tumors while depositing lower dose to normal tissues such as kidneys. Such unique biodistribution is ideally suited for chemoradiation therapy. We hypothesized that the development of a NP formulation of cisplatin can improve therapeutic efficacy and lower the toxicity of cisplatin-based chemoradiation therapy. Materials/Methods: We have developed a novel formulation of cisplatin using the Polysilsesquoxane (PSQ) NP platform. The cisplatin-PSQ NPs were characterized physically using transmission electron microscopy. Its drug release profile was determined. First, we evaluated cisplatin-PSQ NP as a radiosensitizer in vitro using non-small cell lung cancer (NSCLC) cells lines H460 and A549. We then compared the toxicity profiles of cisplatin-PSQ NP to that of cisplatin in vivo. The efficacy of cisplatin-PSQ NP in chemoradiation therapy was compared to that of cisplatin using mouse models of NSCLC. Results: Cisplatin-PSQ NPs were w65 nm in diameter with cisplatin loading of up to 42% (weight) of NP. The cisplatin-PSQ NPs were highly stable with minimal drug release in neutral pH. Cisplatin release was rapid from NPs in reducing environments similar to that of tumor. In vitro evaluation showed cisplatin-PSQ NP is an excellent radiosensitizer with radiation survival curves similar to that of cisplatin. Toxicity evaluations showed cisplatin-PSQ NP has a significantly lower toxicity overall toxicity profile than that of cisplatin. Furthermore, cisplatin-PSQ NP has lower renal toxicity than cisplatin. Lastly, we demonstrated that cisplatin-PSQ NP is more effective than cisplatin in chemoradiation therapy using two mouse xenograft models of NSCLC. Conclusions: We have engineered a novel NP formulation of cisplatin. Cisplatin-PSQ NP has been shown to have lower toxicity and higher efficacy than cisplatin in chemoradiation therapy using NSCLC as a model disease. We believe cisplatin-PSQ is a promising radiosensitizer with high potential for clinical translation. Author Disclosure: A.Z. Wang: P. Ownership Other; Co-Founder, Coordination Therapeutics, Inc. J. Della Rocca: None. N.D. Cummings: None. R. Sukumar: None. M.E. Werner: None. W. Lin: P. Ownership Other; CoFounder, Coordination Therapeutics, Inc.