Endogenous lung surfactant inspired pH responsive nanovesicle aerosols: Pulmonary compatible and site-specific drug delivery in lung metastases

Abstract

Concerns related to pulmonary toxicity and non-specificity of nanoparticles have limited their clinical applications for aerosol delivery of chemotherapeutics in lung cancer. We hypothesized that pulmonary surfactant mimetic nanoparticles that offer pH responsive release specifically in tumor may be a possible solution to overcome these issues. We therefore developed lung surfactant mimetic and pH responsive lipid nanovesicles for aerosol delivery of paclitaxel in metastatic lung cancer. 100–200 nm sized nanovesicles showed improved fusogenicity and cytosolic drug release, specifically with cancer cells, thereby resulting in improved cytotoxicity of paclitaxel in B16F10 murine melanoma cells and cytocompatibility with normal lung fibroblasts (MRC 5). The nanovesicles showed airway patency similar to that of endogenous pulmonary surfactant and did not elicit inflammatory response in alveolar macrophages. Their aerosol administration while significantly improving the biodistribution of paclitaxel in comparison to Taxol (i.v.), also showed significantly higher metastastes inhibition (~75%) in comparison to that of i.v. Taxol and i.v. Abraxane. No signs of interstitial pulmonary fiborisis, chronic inflammation and any other pulmonary toxicity were observed with nanovesicle formulation. Overall, these nanovesicles may be a potential platform to efficiently deliver hydrophobic drugs as aerosol in metastatic lung cancer and other lung diseases, without causing pulmonary toxicity.

Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities

“…Inhaled delivery of drug-loaded nanoparticles led to lower drug concentrations in non-targeted sites (liver, spleen and plasma) compared with intravenous paclitaxel solution. Drug-loaded nanoparticles showed no lung toxicity [96] .…”

“…These nanovesicles fuse with the cell plasma membrane and lysosomal membrane at low pH, thus providing site-specific and triggered delivery of anticancer drugs to cancer cells [93][94][95] . It has been demonstrated that pulmonary surfactant mimetic pHsensitive nanoparticles are cytotoxic to lung tumor cells while being compatible with healthy lung cells, indicating a selective toxicity of the developed formulation to lung cancer cells [96] .…”

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

“…(27) Inhaled (IH) paclitaxel for locoregional NSCLC treatment has demonstrated proof of principle in a variety of preclinical models. (28)(29)(30)(31)(32)(33)(34)(35)(36)(37) To evaluate its potential as an IH lung cancer therapy, NanoPac suspension was administered to healthy rats through nebulized inhalation to determine the pharmacokinetic profile in both lung tissue and circulating plasma. Quantifiable levels of paclitaxel were detected in lung tissue at final necropsy, 2 weeks after single administration.…”

Loco-regional administration of nanomedicines for the treatment of lung cancer

“…The aerosol treatment (10 ml of 0.5 mg/ml paclitaxel liposomal formulation for 5 consecutive days every week) was compared to intravenous treatment with two commercial formulations of the drug Taxol Õ and Abraxane Õ (10 mg/kg once every 3 d). The aerosol treatment showed no major pulmonary toxicities such as fibrosis and chronic inflammation and produced a significant reduction in the number of metastases and lung surface occupied by the lesions, with an overall metastases inhibition of nearly 75%, superior to the parenteral treatment with both commercial product (around 50% inhibition for both treatments) (Joshi et al, 2014).…”