In Vivo Pulmonary Delivery and Magnetic-Targeting of Dry Powder Nano-in-Microparticles.

Dominique N Price,Loreen R Stromberg,Pavan Muttil,Nitesh K Kunda

doi:10.1021/acs.molpharmaceut.7b00532

Dominique N Price, Loreen R Stromberg + Show 2 more

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https://doi.org/10.1021/acs.molpharmaceut.7b00532

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Abstract

This brief communication evaluates the cytotoxicity and targeting capability of a dry powder chemotherapeutic. Nano-in-microparticles (NIMs) are a dry powder drug delivery vehicle containing superparamagnetic iron oxide nanoparticles (SPIONs) and either doxorubicin (w/w solids) or fluorescent nanospheres (w/v during formulation; as a drug surrogate) in a lactose matrix. In vitro cytotoxicity was evaluated in A549 adenocarcinoma cells using MTS and LDH assays to assess viability and toxicity after 48 h of NIMs exposure. In vivo magnetic-field-dependent targeting of inhaled NIMs was evaluated in a healthy mouse model. Mice were endotracheally administered fluorescently labeled NIMs either as a dry powder or a liquid aerosol in the presence of an external magnet placed over the left lung. Quantification of fluorescence and iron showed a significant increase in both fluorescence intensity and iron content to the left magnetized lung. In comparison, we observed decreased targeting of fluorescent nanospheres to the left lung from an aerosolized liquid suspension, due to the dissociation of SPIONs and nanoparticles during pulmonary administration. We conclude that dry powder NIMs maintain the therapeutic cytotoxicity of doxorubicin and can be better targeted to specific regions of the lung in the presence of a magnetic field, compared to a liquid suspension.

Highlights

Lung cancer is the second most commonly diagnosed cancer in both men and women, and it has the highest mortality rate compared to all other types of cancer accounting for 26.5% of all cancer deaths.[1−3] Conventional chemotherapy for lung cancer is administered intravenously and does not distinguish between cancerous and healthy cells
The high concentrations of chemotherapeutic agents that are required for systemic administration often lead to non-specific adverse effects, while lung tumor microenvironments that are distantly located from capillaries receive subtherapeutic drug concentrations
Pulmonary delivery of chemotherapy has been evaluated in human trials for the treatment of lung cancer.[10−15] A phase I/II study of inhaled doxorubicin combined with systemic platinum-based therapy was administered to twenty-eight patients with advanced non-small cell lung cancer.[11]

Summary

Introduction

Lung cancer is the second most commonly diagnosed cancer in both men and women, and it has the highest mortality rate compared to all other types of cancer accounting for 26.5% of all cancer deaths.[1−3] Conventional chemotherapy for lung cancer is administered intravenously and does not distinguish between cancerous and healthy cells. Pulmonary drug delivery has been used to treat respiratory diseases, such as asthma and microbial infections, as well as systemic diseases.[4−9] The lungs are well-suited for drug delivery due to their large surface area, thin alveolar epithelium, permeable membrane, and extensive vasculature, which allow substantial and rapid drug absorption for increased local and systemic efficacy.[9] Pulmonary delivery of chemotherapy has been evaluated in human trials for the treatment of lung cancer.[10−15] A phase I/II study of inhaled doxorubicin combined with systemic platinum-based therapy was administered to twenty-eight patients with advanced non-small cell lung cancer.[11] while the results of this localized delivery were promising, a few patients experienced doselimiting pulmonary-toxicity.

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