Inhaled Submicron Particle Paclitaxel (NanoPac) Induces Tumor Regression and Immune Cell Infiltration in an Orthotopic Athymic Nude Rat Model of Non-Small Cell Lung Cancer

Abstract

Background: This study evaluated the antineoplastic and immunostimulatory effects of inhaled (IH) submicron particle paclitaxel (NanoPac Ò) in an orthotopic non-small cell lung cancer rodent model. Methods: Male nude rats were whole body irradiated, intratracheally instilled with Calu-3 cancer cells and divided into six treatment arms (n ¼ 20 each): no treatment (Group 1); intravenous nab-paclitaxel at 5.0 mg/kg once weekly for 3 weeks (Group 2); IH NanoPac at 0.5 or 1.0 mg/kg, once weekly for 4 weeks (Groups 3 and 4), or twice weekly for 4 weeks (Groups 5 and 6). Upon necropsy, left lungs were paraffin embedded, serially sectioned, and stained for histopathological examination. A subset was evaluated by immunohistochemistry (IHC), anti-pan cytokeratin staining AE1/AE3 + tumor cells and CD11b + staining dendritic cells, natural killer lymphocytes, and macrophage immune cells (n ¼ 2, Group 1; n ¼ 3 each for Groups 2-6). BCL-6 staining identified B lymphocytes (n ¼ 1 in Groups 1, 2, and 6). Results: All animals survived to scheduled necropsy, exhibited no adverse clinical observations due to treatment, and gained weight at the same rate throughout the study. Histopathological evaluation of Group 1 lung samples was consistent with unabated tumor growth. Group 2 exhibited regression in 10% of animals (n ¼ 2/ 20). IH NanoPac-treated groups exhibited significantly higher tumor regression incidence per group (n ¼ 11-13/ 20; p < 0.05, v 2). IHC subset analysis revealed tumor-nodule cluster separation, irregular borders between tumor and non-neoplastic tissue, and an increased density of infiltrating CD11b + cells in Group 2 animals (n ¼ 2/3) and in all IH NanoPac-treated animals reviewed (n ¼ 3/3 per group). A single animal in Group 4 and Group 6 exhibited signs of pathological complete response at necropsy with organizing stroma and immune cells replacing areas presumed to have previously contained adenocarcinoma nodules. Conclusion: Tumor regression and immune cell infiltration were observed in all treatment groups, with an increased incidence noted in animals receiving IH submicron particle paclitaxel treatment.

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood

“…Evaluation of tumor tissues from these animals determined that IT NanoDoce administration resulted in high levels (> 1500 μg/g of tissue) of docetaxel within the tumor up to 50 days after treatment [1]. Further, we found that nebulized submicron particle paclitaxel (NanoPac®) substantially reduced or eradicated Calu-3 non-small cell lung cancer (NSCLC) tumors in immunocompromised mice which did not occur following IV administration of nab-paclitaxel [2,3]. These previous studies were performed in rodents with genetically depleted T cells, whereas here we evaluated the response of an intact immune system to direct injection of NanoDoce compared to IV docetaxel in a Renca syngeneic model.…”

“…Prior to the point where group MTV = 2000 mm 3 , two treatment-related (TR) deaths occurred: one animal in the docetaxel-2°group was found dead on Day 6 and one animal on Day 18 in the IT/PT NanoDoce-2 group was euthanized on Day 18 due to severe BW loss. In IT NanoDoce-treated animals maintained on study beyond when control group MTV > 2000 mm 3 , one IT NanoDoce-2 was euthanized on Day 28 due to BW loss. Several animals across various treatment groups had similar necropsy findings of enlarged spleen and pale liver, kidneys and lungs at study endpoint (TV > 2000 mm 3 ).…”

“…In IT NanoDoce-treated animals maintained on study beyond when control group MTV > 2000 mm 3 , one IT NanoDoce-2 was euthanized on Day 28 due to BW loss. Several animals across various treatment groups had similar necropsy findings of enlarged spleen and pale liver, kidneys and lungs at study endpoint (TV > 2000 mm 3 ).…”

Enhanced Tumor Regression and Immune Cell Infiltration by Inhaled Submicron Particle Paclitaxel in an Orthotopic Athymic Nude Rat Model of Non-Small Cell Lung Cancer (NSCLC)

“…William Johnston 1 , James Verco 1 , Gere diZerega 1,2 , Michael Frost 5 , Michael Baltezor 2,3 , Philip Kuehl 4…”

“…1 US Biotest, Inc., San Luis Obispo, CA, USA; 2 Nanology, LLC., Fort Worth, TX, USA; 3 CritiTech, Inc., Lawrence, KS, USA; 4 Lovelace Biomedical, Albuquerque, NM, USA; 5 Western Diagnostic Services Laboratory, Santa Maria, CA, USA 19.9 5,800 23,112…”