CARMUSTINE LOADED NANOSIZE LIPID VESICLES SHOWED PREFERENTIAL CYTOTOXICITY AND INTERNALIZATION IN U87MG CELL LINE ALONG WITH IMPROVED PHARMACOKINETIC PROFILE IN MICE: A STRATEGY FOR TREATMENT OF GLIOMA
Keywords:Carmustine, Nanosize lipid vesicles, Glioma, Cytotoxicity, Pharmacokinetic
Objective: Successful treatment of glioma still remains a tough challenge. The present study aims at the development and evaluation of carmustine loaded nanosize phospholipid vesicles (CNLVs) for the treatment of glioma.
Methods: The experimental NLVs were developed by conventional lipid layer hydration technique and were characterized by different in vitro tools such as diffraction light scattering (DLS), zeta potential, field emission scanning electron microscopy (FESEM), cryo-transmission electron microscopy (cryo-TEM), in vitro drug loading capacity, drug release study etc. In vitro cytotoxicity and cellular uptake of the optimized drug-loaded NLVs were carried out in U87MG human glioblastoma cell line. In vivo pharmacokinetic study was conducted in Swiss albino mice.
Results: DLS data showed an average vesicle diameter of 92 nm with narrow size distribution. Optimized CNLVs were spherical in shape with a smooth surface as depicted from FESEM data. Cryo-TEM study confirmed formation of unilamellar vesicles with intact outer bilayer. A reasonable drug loading of 7.8 % was reported for the optimized CNLVs along with a sustained release of CS over a 48 h study period. In vitro cytotoxicity assay revealed a considerable higher toxicity of CNLVs than free drugs in the U87MG cells. Confocal microscopy showed a satisfactory internalization of the optimized drug-loaded NLVs in the tested cell line. Pharmacokinetic data demonstrated an enhanced mean residence time of optimized CNLVs in blood than free drug.
Conclusion: Results depicted the potential of experimental CNLVs for the treatment of glioma after further in vivo tests.
Wang D, Wang C, Wang L, Chen Y. A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment. Drug Delivery 2019;26:551–65.
American Cancer Society's publication, Cancer Facts and fig.; 2020.
Hu X, Yang F, Liao Y, Li L, Zhang L. Cholesterol-PEG commodified poly (Nbutyl) cyanoacrylate nanoparticles for brain delivery: in vitro and in vivo evaluations. Drug Delivery 2017;24:121–32.
Keerthana V, Dhanalakshmi S, Harikrishnan N. A perspective review on applications of nanoparticle mediated drug delivery to the CNS. Int J Curr Pharm Res 2020;12:1-4.
Jain KK. Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine 2012;7:1225-33.
Hao Y, Wang L, Zhao Y, Meng D, Li D, Li H, et al. Targeted imaging and chemophototherapy of brain cancer by a multifunctional drug delivery system. Macromol Biosci 2015;15:1571–85.
Sonali S, Singh RP, Singh N, Sharma G, Vijayakumar MR, Koch B, et al. Transferrin liposomes of docetaxel for brain targeted cancer applications: formulation and brain theranostics. Drug Delivery 2016;23:1261-71.
Bondì ML, Di Gesu R, Craparo EF. Lipid nanoparticles for drug targeting to the brain. Methods Enzymol 2012;508:229-51.
Laouini A, Jaafar Maalej C, Limayem Blouza I, Sfar S, Charcosset C, Fessi H. Preparation, characterization and applications of liposomes: state of the art. J Colloid Sci Biotechnol 2012;1:147-68.
Shinde AJ, Patil NC. Design and development of nanostructured lipid carrier containing triamcinolone acetonide. Int J Pharm Pharm Sci 2019;11:26-35.
Yi S, Yang F, Jie C, Zhang G. A novel strategy to the formulation of carmustine and bioactive nanoparticles co-loaded PLGA biocomposite spheres for targeting drug delivery to glioma treatment and nursing care. Artif Cells Nanomed Biotechnol 2019;47:3438–47.
De Vita VT, Carbone PP, Owens Jr AH, Gold GL, Krant MJ, Edmonson J. Clinical trials with 1,3-bis(2-chloroethyl)-1-nitrosourea, NSC-409962. Cancer Res 1965;25:1876–81.
O’Driscoll BR, Kalra S, Gattamaneni HR, Woodcock AA. Late carmustine lung fibrosis: Age at treatment may influence severity and survival. Chest 1995;107:1355–7.
Shaw TK, Mandal D, Dey G, Pal MM, Paul P, Chakraborty S, et al. Successful delivery of docetaxel to rat brain using experimentally developed nanoliposome: a treatment strategy for brain tumor. Drug Delivery 2017;24:346–57.
Satapathy BS, Mukherjee B, Baishya R, Debnath MC, Dey NS, Maji R. Lipid nano carrier-based transport of docetaxel across the blood-brain barrier. RSC Adv 2016;6:85261–74.
Khan R, Irchhaiya R. In vitro in vivo evaluation of niosomal formulation of famotidine. Int J Pharm Pharm Sci 2020;12:15-22.
Sailaja PB, Jeevana JB. Development and in vitro evaluation of 5-fluorouracil nanoparticles by salting out technique. Asian J Pharm Clin Res 2020;13:166-71.
Praveen S, Gowda DV, Siddaramaiah H, Hemalatha S. Ziprasidone hydrochloride loaded nanostructured lipid carriers (NLCS) for intranasal delivery: optimization and in vivo studies. Int J Appl Pharm 2020;12:31-41.
Maji R, Dey NS, Satapathy BS, Mukherjee B, Mondal S. Preparation and characterization of tamoxifen citrate loaded nanoparticles for breast cancer therapy. Int J Nanomed 2014;25:3107-18.
Abraham S, Deveswaran R, Anbu J, Furtado S, Bharath S. Pharmacokinetic studies of a chronotherapeutic drug delivery system of lornoxicam by LC-MS/MS method. Int J Appl Pharm 2018;10:88-93.
Athmakur H, Kondapi AK. Carmustine loaded lactoferrin nanoparticles demonstrates an enhanced antiproliferative activity against glioblastoma in vitro. Int J Appl Pharm 2018;10:234-1.
Zena HS, Hussein A, Sarmad GA, Hamid NO. The effects of the antibody directed nanosphere carrier for the combined carmustine-busulfan in human lung cancer tissue culture. Ann Trop Med Public Health 2019;22:1-12.
Zhirong Z, Yu W, Sanjun S, Jianfeng H, Zhirong Z, Xun S. Co-delivery of adenovirus and carmustine by anionic liposomes with synergistic anti-tumor effects. Pharm Res 2012;29:145–7.