Abstract 5533: A local chemotherapy with hyaluronan-cisplatin conjugate significantly attenuates growth of lung adenocarcinoma xenografts in mouse model

Abstract

Nanoparticle-based chemotherapy, while promising, remains clinically unsuccessful, mainly due to a lack of targeted delivery methods of the therapeutics into cancer tissues and the side effect of chemotherapeutics. We have demonstrated that the nanoparticle formulation with hyaluronan-cisplatin conjugates (HylaPlat) is suggested to be an effective chemotherapeutic delivery method in breast cancer mouse models (Cai, et al., J Surg Res., 2008; Cai, et al., Ther Deliv, 2011). The objectives of the present study were to examine the growth inhibition efficacy of HylaPlat formulation on lung adenocarcinoma cells in cell culture and to examine the therapeutic efficiency of the local administration of HylaPlat on lung adenocarcinoma in mice. Effect of the HylaPlat on the growth of lung carcinoma was evaluated using Lewis Lung carcinoma (LLC) cells in 2D culture and 3D spheroid cell culture, as well as, orthotopic autografts in C57BL/6 mice lungs. Cell culture studies clarified that the HylaPlat effectively attenuated cell growth in 2D and 3D spheroid culture with IC50 of 0.35μM and 1.35 μM, respectively; whereas control cisplatin-dependent growth inhibition was achieved with several fold higher concentrations (IC50 1.64 and 3.6 μM, respectively). The 3D spheroid cell culture study also revealed that the treatment with HylaPlat induced apoptosis in the cells located on the peripheral area of the spheroid first, this effect lasted for several days. A single intratracheal administration of 7.5mg/kg HylaPlat (1mg cisplatin equivalent/kg) seven days after LLC cell inoculation almost completely inhibited growth of LLC autografts in the mouse lungs. Histological analysis of dissected lungs revealed that a small number of microscopic tumor nodules were detected in the treated mouse lungs, whereas several large tumors were detected in the untreated control mouse lungs. Normal lung architectures of the trachea, bronchioles and alveoli were maintained in the treated mice although small inflammation spots can be detected at peripheral areas. Apoptotic index was significantly higher in the treated tumors than PBS treated control tumors, suggesting that cisplatin was successfully delivered to the tumor tissues by nanoparticle formulated HylaPlat and caused apoptosis of tumor cells. The pharmacokinetics of cisplatin 14 days after intratracheal administration of HylaPlat is under investigation. Taken together, the current study suggests that an intratracheal administration of HylaPlat nanoparticles offer an effective strategy for lung cancer treatment. This work was supported by the Kansas State University Johnson Cancer Research Center, Kansas Bioscience Authority Collaborative Cancer Research grant, 1R01CA173292 (LF) and American Cancer Society RSG-08-133-01-CDD (LF).

Citation Format: Susumu Ishiguro, Deepthi Uppalapati, Shuang Cai, Katie Turner, Jacob Hodge, Laird Forest, Masaaki Tamura. A local chemotherapy with hyaluronan-cisplatin conjugate significantly attenuates growth of lung adenocarcinoma xenografts in mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5533. doi:10.1158/1538-7445.AM2015-5533