Endogenous lung surfactant inspired pH responsive nanovesicle aerosols: pulmonary compatible and site-specific drug delivery in lung metastases.
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.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Nitin
N
Joshi
Department of Cancer Pharmacology, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai 400063, India.
Nitesh
N
Shirsath
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Ankur
A
Singh
1] Department of Cancer Pharmacology, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai 400063, India [2] Target Identification Group, Piramal life Sciences, 1-Nirlon Complex, Goregaon, Mumbai 400063, India.
Kalpana S
KS
Joshi
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Rinti
R
Banerjee
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D054118:Nanospheres / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011663:Pulmonary Surfactants / Q000737:chemistry; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D000336:Aerosols; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D010714:Phosphatidylethanolamines; D011663:Pulmonary Surfactants; D015060:1,2-Dipalmitoylphosphatidylcholine; D017239:Paclitaxel