Abstract 4482: Development of localized cisplatin chemotherapy: from benchside to investigational new drug application
Authors: Cai Shuang , Bryan Jeffrey , Aries Daniel , Forrest Laird 
Published: May 2015

Abstract
Many cancers preferentially spread to the lymphatics before systemic dissemination. The purpose of this study is to develop intralymphatically-targeted cisplatin nanoparticles for treating locally advanced head and neck cancer. This treatment methodology may significantly reduce the side effects and increase the efficacy of cisplatin-based chemotherapy in both humans and companion animals, compared to conventional intravenous chemotherapies. Cisplatin was chemically conjugated to hyaluronan (HA) to form hyaluronan-cisplatin (HA-Pt) nanoparticles. The nanoparticles were purified and concentrated using a tangential flow filtration system. The cisplatin substitution degree, particle size, molecular weight, viscosity, osmolality, sterility, bioburden, particulate content, impurity profiles, and stability of the formulation in the presence of various excipients were determined. All analytical methods utilized were fully validated according to FDA and/or USP guidelines. The pharmacokinetics, biodistribution and safety of subcutaneously injected HA-Pt were evaluated in animals. Anti-cancer efficacy of HA-Pt was determined in mice bearing cisplatin sensitive xenografts (1/wk for 3wks; 3.5mg/kg). Canines with spontaneously-occurring limb lymphomas were given a single 0.85-mg/kg subcutaneous dose peritumorally. Canines with spontaneously-occurring oral squamous cell carcinoma, oral melanoma, or nasal tumors received 3 doses at 10 to 15 mg/m2, peritumorally. The cisplatin conjugation degree on HA was 15-20 w/w%. HA-Pt demonstrated antiproliferative efficacy similar to standard cisplatin in vitro with sustained release of cisplatin (t1/2=10h). The characteristics of HA-Pt meet FDA requirements for injectable formulations. HA-Pt resulted in higher plasma area-under-the-curve (AUC) and lower Cmax in rats. Murine xenografts demonstrated improved complete and partial responses to HA-Pt treatment compared to standard cisplatin therapy. The HA-Pt reduced Cmax 5.5 fold and increased the canine plasma AUC of cisplatin 5.4 fold and the lymph node concentration 18 fold compared to i.v. cisplatin. The tumor:plasma ratio in canines was 429, indicating the nanoparticles concentrated drug within the tumor. A single injection of HA-Pt resulted in size reduction of the metastatic lymph nodes of canine oral melanoma. After the completion of 3 treatments, the canine oral tumor was completely eradicated (no recurrence within a year) and swelling was greatly reduced. Stable disease was observed for most of the dogs. This study demonstrates that subcutaneous delivery of HA-Pt formulations may be a promising treatment regimen to improve tumor drug accumulation and therapeutic efficacy. The successful completion of a series of GLP rodent and canine study will warrant a submission of an Investigational New Drug Application to the FDA.
Citation Format: Shuang Cai, Jeffrey Bryan, Daniel Aries, Laird Forrest. Development of localized cisplatin chemotherapy: from benchside to investigational new drug application. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4482. doi:10.1158/1538-7445.AM2014-4482