Background: Inhaled chemotherapeutics may enhance pulmonary drug exposure to malignant lesions in the lung without substantially contributing to systemic toxicities. The pharmacokinetic profile of inhaled submicron particle paclitaxel (NanoPac ® ) in healthy rodent plasma and lung tissue is evaluated here to determine administration proof-of-principle. Methods: Healthy male Sprague Dawley rats received paclitaxel in one of three arms: intravenous nab-paclitaxel at 2.9 mg/kg (IVnP), inhaled NanoPac low dose (IHNP-LD) at 0.38 mg/kg, or inhaled NanoPac high dose (IHNP-HD) at 1.18 mg/kg. Plasma and lung tissue paclitaxel concentrations were determined using ultraperformance liquid chromatography tandem mass spectrometry from animals sacrificed at 10 time points ranging up to 2 weeks after administration. Peak concentration (C max ), apparent residence half-life (T 1/2 ), exposure (AUC (last) ), and dose-normalized exposure (AUC D(last) ) were determined. Pulmonary histopathology was performed on rats sacrificed at the 336-hour time point. Results: Paclitaxel was detectable and quantifiable in the rat lung for both inhaled NanoPac arms sampled at the final necropsy, 336 hours postadministration. Substantial paclitaxel deposition and retention resulted in an order of magnitude increase in dose-normalized pulmonary exposure over IVnP. Inhaled NanoPac arms had an order of magnitude lower plasma C max than IVnP, but followed a similar plasma T 1/2 clearance (quantifiable only to 72 hours postadministration). Pulmonary histopathology found all treated animals indistinguishable from treatment-naive rats. Conclusion: In the rodent model, inhaled NanoPac demonstrated substantial deposition and retention of paclitaxel in sampled lung tissue. Further research to determine NanoPac's toxicity profile and potential efficacy as lung cancer therapy is underway.
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.
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