Regular ArticleLomustine (LMT) is a nitrosourea of compound, mainly used in brain tumors, resistant or relapsed Hodgkin's disease, other lymphomas, lung cancer, malignant melanoma and various solid tumors. LMT is used either alone or in combination with other cytostatic drugs. Unfortunately, it also has serious untoward side effects and is rather a toxic compound, and the therapeutic index, the ratio between the toxic dose and the therapeutic dose, is not very favorable. Potential benefits of biodegradable polymeric nanoparticles have attracted considerable attention as colloidal drug delivery. Nanoparticles can be transported via the circulation to different body sites. Chitosan nanoparticles (NPs) have been investigated for targeted delivery to the colon, mucosa in cancer therapy for vaccine delivery, and gene delivery. Additionally, such systems have the ability to control the rate of drug administration, thus controlling the duration of the therapeutic effect, and also deliver the drug to specific sites. [1][2][3][4][5][6] The ionotropic gelation method has already been established to prepare chitosan nanoparticles that uses protonized -NH 3 ϩ to interact with an anion such as tripolyphosphate. 7) In addition, reversible physical crosslinking by electrostatic interaction, instead of chemical crosslinking, is applied to prevent possible toxicity of reagents and other undesirable effects. 8,9) To decrease the size variation and polydispersity of nanoparticles, ultrasonication at increasing reaction time or radiation amplitude has been used. Tsai et al. 10) prepared chitosan nanoparticles by modified ionic gelation with mechanical stirring with ultrasonication. Other means to increase the shearing effects are high pressure homogenization instead stirring.As a non-ionic hydrophilic polymer, polyethylene glycol (PEG) exhibits outstanding protein resistance, minimal toxicity and immunogenicity. PEG coated nanoparticles have been found to be of great potential in therapeutic application for controlled release of drugs and site-specific drug delivery. 11)PEG chains that have attached to the surface or formed the corona of a nanoparticle exhibit rapid motion in aqueous media and have a large excluded volume, and steric repulsion results from a loss of configurational entropy of the bound PEG chains.12) In addition, the hydrophilic PEG can form a hydrated outer shell, which protects the nanoparticles from being quickly uptaken by the reticuloendothelial system extending the half-life of drugs, and altering their tissue distribution. 13)This study aims to develop a LMT loaded chitosan nanoparticles (LCNPs) by ionic gelation method with homogenization to increase the antineoplasitc efficiency of LMT. Particle size and morphology of the fabricated nanoparticles were studied by DLS, SEM and TEM. Effect of various parameters such as chitosan (CH)/tripolyphosphate (TPP) ratio, PEG coating, and homogenization on nanoparticle size and encapsulation were studied. The interaction between LMT and PEG-chitosan and in-vitro rele...

This work was focused on identification and evaluation of process parameters of modified nanoprecipitation method, for fabrication of lomustine nanoparticles, with the aim of reducing cancer cell viability at low concentration of lomustine. The parameters controlling particle size, mostly in nanosize, were solvent/nonsolvent composition and emulsification speed of homogenizer along with aqueous phase volume. This controlled particle size is below 250 nm. The stabilizer concentration controlled particle size is within 68 nm ± 0.89 to 137 ± 0.94 nm with PDI 0.06 ± 0.008 to 0.25 ± 0.001. But, the stabilizer addition mode showed more uniform size distribution with PDI 0.085 ± 0.004. Entrapment efficiency was maintained well above 47 ± 0.23%. The drug release pattern was monophasic with controlled release over 24 hrs. In the method used, drug content was affected by ratio of polymer to drug to organic solvent, as well as homogenization speed and time. Percentage viable cells of L132 human lung cancer cell line remained, were only 5% at 100 µg/ml lomustine equivalent PLA nanoparticles. ethanol as a cosolvent, homogenization speed and time were evaluated affecting the particle size, encapsulation efficiency and in vitro drug release.

This study was aimed to develop lomustine loaded chitosan nanoparticles using a homogenization and spray drying technique. Effect of crosslinking agents (sodium tripolyphosphate (TPP), and sodium hexametaphosphate (HMP)) were studied on the leaching of drug, water uptake of hydrogels, drug release from matrix and its mechanism. Nanoparticles were obtained in the average size range of 111±16.2 to 942±11.7 nm with polydispersity index (PDI) from 0.116±0.039 to 0.517±0.037. Zeta potential of nanoparticles was ranged from 29.0±1.1 to 56.0±1.1 mV. The % encapsulation effi ciency of nanoparticles ranged between 58±0.88% and 96±0.51%.nanoparticles were coated with PEG 6000 to modulate drug release. Swelling index of chitosan-TPP and chitosan-TPP-PEG nanoparticles was about 428% and 350% over the 4 h and it was more (about 465% and 395%) for chitosan-HMP and chitosan-HMP-PEG nanoparticles. Drug release was sustained and diffusion controlled. Optimized formulation was tested for anticancer activity and drug retention study. Cytotoxicity on human lung cancer cell line L132 was studied by trypan blue dye exclusion test. Drug loaded nanoparticles killed L132 cells more effi ciently than the corresponding drug alone (p< 0.05). Due to the increased surface area lomustine loaded TPP and HMP crosslinked chitosan nanoparticles showed better anticancer activity.

The incorporation of lomustine, a hydrophobic anticancer drug into PLGA nanoparticles by interfacial deposition method was optimized. Based on the optimal parameters, it was found that lomustine-PLGA nanoparticles with acceptable properties could be obtained. Optimization of formulation variables to control the size and drug entrapment efficiency of the prepared nanoparticles seems to be based on the same scientific principles as drug-loaded nanoparticles prepared by nanoprecipitation, solvent evaporation method. The process was the most important factor to control the particle size, while both the drug-polymer interaction and the partition of drug in organic and aqueous phases were the crucial factors to govern the drug entrapment efficiency. PLGA concentration at lower level (100 mg), 1:5 organic phase: aqueous ratio, 1%w/v PVA concentration, 3%w/v pluronic F68 achieved smaller particle size. Additionally, L:G ratio of PLGA 75:25, lower volume of organic solvent (1:10 organic phase: aqueous phase), higher initial drug content (10 mg) enhanced the drug entrapment efficiency and maintained lomustine concentration in blood for an extended time period, elevated lomustine concentration in lungs and slowed the elimination of lomustine. The biodistribution profiles of prepared nanoparticles in albino mice showed higher plasma drug concentration for longer period of time, elevated drug concentration in lungs and slow elimination from kidney. No toxic effects of prepared nanoparticles were observed in histopathological examination of lungs and kidney. The systematic investigation reported here promises the development of PLGA nanoparticles loaded with lomustine when tested in Lung Cancer cell line L132 and toxicological/ histopathological studies in albino mice.

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