title: Inhalable nanostructured lipid particles of 9-bromo-noscapine, a tubulin-binding cytotoxic agent: in vitro and in vivo studies.
abstract: 9-Bromo-noscapine (9-Br-Nos) alters tubulin polymerization in non-small cell lung cancer cells differently from noscapine. However, clinical applications of 9-Br-Nos are limited owing to poor aqueous solubility and high lipophilicity that eventually lead to suboptimal therapeutic efficacy at the site of action. Hence, 9-Br-Nos loaded nanostructured lipid particles (9-Br-Nos-NLPs) were prepared by nanoemulsion method to reduce the particle size below 100 nm. To impart the inhalable and rapid release (RR) attributes, 9-Br-Nos-NLPs were treated with spray dried lactose and effervescent excipients to generate, 9-Br-Nos-RR-NLPs. The mean particle and aerodynamic size of 9-Br-Nos-NLPs were measured to be 13.4±3.2 nm and 2.3±1.5 μm, significantly (P<0.05) lower than 19.4±6.1 nm and 3.1±1.8 μm of 9-Br-Nos-RR-NLPs. In addition, zeta-potential of 9-Br-Nos-NLPs was examined to be -9.54±0.16 mV, significantly (P<0.05) lower than -7.23±0.10 mV of 9-Br-Nos-RR-NLPs. Hence, both formulations were found to be optimum for pulmonary delivery through inhalation route of administration. Next, 9-Br-Nos-RR-NLPs exhibited enhanced cytotoxicity, apoptosis and cellular uptake in A549, lung cancer cells, as compared to 9-Br-Nos-NLPs and 9-Br-Nos suspension. This may be attributed to enhanced drug delivery and internalization character of 9-Br-Nos-RR-NLPs by energy-dependent endocytosis and passive diffusion mechanism. Pharmacokinetic and distribution analysis demonstrated the superiority of 9-Br-Nos-RR-NLPs that exhibited ∼1.12 and ∼1.75-folds enhancement in half-life of the drug as compared to 9-Br-Nos-NLPs and 9-Br-Nos powder following inhalation route. Continuation to this, 9-Br-Nos-RR-NLPs also displayed ∼3.75-fold increment in half-life of the drug in lungs, as compared to 9-Br-Nos suspension following intravenous route of administration. Furthermore, enhanced drug exposure was measured in terms of AUC(last) in lungs following administration of 9-Br-Nos-RR-NLPs, as compared to 9-Br-Nos-NLPs, 9-Br-Nos powder and 9-Br-Nos suspension. This may be attributed to rapid dispersion, enhanced dissolution and deep lung deposition of nanoparticles following inhalation route. Therefore, inhalable 9-Br-Nos-RR-NLPs claims further in depth in vivo tumor regression study to scale up the technology for clinical applications.
authors.affiliation: Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Jyoti
authors.affiliation: Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India.
authors.forename: Karanvir
authors.initials: K
authors.lastname: Kaur
authors.affiliation: SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur, India.
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Pandey
authors.affiliation: Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India.
authors.forename: Upendra Kumar
authors.initials: UK
authors.lastname: Jain
authors.affiliation: Dr. BR Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.affiliation: Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India. Electronic address: jitenderpharmacy@gmail.com.
authors.forename: Jitender
authors.initials: J
authors.lastname: Madan
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D054879:Halogenation; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009665:Noscapine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010316:Particle Size; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008055:Lipids; D014404:Tubulin; D009665:Noscapine
keywords: 9-Bromo-noscapine; Apoptosis; Cellular uptake; Cytotoxicity; Inhalable nanoparticles; Pharmacokinetics