Lactose-Conjugated PLGA Nanoparticles for Enhanced Delivery of Rifampicin to the Lung for Effective Treatment of Pulmonary Tuberculosis

Lactose conjugated poly(lactic co-glycolic acid) nanoparticles (L-PLGA-NPs) were investigated for lung delivery of rifampicin for effective treatment of pulmonary tuberculosis. Lactose-PLGA conjugate was synthesized using lactose and PLGA and characterized by infrared spectroscopy. L-PLGA-NPs were prepared by the solvent displacement method. NPs were characterized for shape, particle size, zeta potential, and percent drug entrapment. The size of NPs was found to be in the range 121-184 nm and maximum drug payload was found to be 38.4-42.2%. Average size and drug payload was found to be greater in the case of L-PLGA-NPs as compared to unconjugated NPs. The results of the in vitro release profile, which was determined using the dialysis technique, demonstrated that noncoupled NPs release a comparatively higher percent of drug than lactose coupled NPs. Fluorescence studies revealed the enhanced uptake of L-PLGA-NPs in the lung tissue when compared with unmodified PLGA NPs. Intravenous administration of free drug solution resulted in a high concentration of drug in serum while it was much less in the case of PLGA NPs. Coupling of the NPs with lactose significantly enhanced the lung uptake of drug, which is reflected in the recovery of a higher percentage of dose from the lungs as compared to that recovered in the case of uncoupled drug-loaded NPs and plain drug solution.     

Preparation and characterization of teniposide PLGA nanoparticles and their uptake in human glioblastoma U87MG cells

Many studies have demonstrated the uptake mechanisms of various nanoparticle delivery systems with different physicochemical properties in different cells. In this study, we report for the first time the preparation and characterization of teniposide (VM-26) poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and their cellular uptake pathways in human glioblastoma U87MG cells. The nanoparticles prepared with oil-in-water (O/W) single-emulsion solvent evaporation method had a small particle size and spherical shape and provided effective protection against degradation of teniposide in PBS solution. Differential scanning calorimeter (DSC) thermograms concluded that VM-26 was dispersed as amorphous or disordered crystalline phase in the PLGA matrix. A cytotoxicity study revealed that, in a 24h period, blank PLGA NPs had no cytotoxicity, whereas teniposide-loaded PLGA NPs (VM-26-NPs) had U87MG cytotoxicity levels similar to free teniposide. Confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) images showed the distribution and degradation processes of nanoparticles in cells. An endocytosis inhibition test indicated that clathrin-mediated endocytosis and macropinocytosis were the primary modes of engulfment involved in the internalization of VM-26-NPs. Our findings suggest that PLGA nanoparticles containing a sustained release formula of teniposide may multiplex the therapeutic effect and ultimately degrade in lysosomal within human glioblastoma U87MG cells.     

紫杉醇PLGA纳米粒的处方优化与评价

目的 采用生物可降解材料乳酸-羟基乙酸共聚物(PLGA)为载体,比较不同的制备方法和工艺对紫杉醇(PTX)PLGA纳米粒(PTX-PLGA NPs)粒径的影响,筛选出最优制备工艺,并考察所制备纳米粒的体外表征以及对人源胃癌细胞SGC-7901的抗肿瘤效果,为紫杉醇缓释制剂在胃癌中的开发提供一定的实验基础.方法 采用单因...     

Delivery of a peptide via poly(d,l-lactic-co-glycolic) acid nanoparticles enhances its dendritic cell–stimulatory capacity

Nanoparticles (NPs) are attractive carriers for vaccines. We have previously shown that a short peptide (Hp91) activates dendritic cells (DCs), which are critical for initiation of immune responses. In an effort to develop Hp91 as a vaccine adjuvant with NP carriers, we evaluated its activity when encapsulated in or conjugated to the surface of poly(d,l-lactic-co-glycolic) acid (PLGA) NPs. We found that Hp91, when encapsulated in or conjugated to the surface of PLGA-NPs, not only activates both human and mouse DCs, but is in fact more potent than free Hp91. Hp91 packaged within NPs was about fivefold more potent than the free peptide, and Hp91 conjugated to the surface of NPs was ～20-fold more potent than free Hp91. Because of their capacity to activate DCs, such NP-Hp91 systems are promising as delivery vehicles for subunit vaccines against infectious disease or cancer.From the Clinical EditorIn this paper, nanoparticle-based dendritic cell activating vaccines are described and discussed. The authors report that the presented PLGA NP based vaccine constructs increase the potency of the studied vaccine by up to 20-fold, making them promising as delivery vehicles for subunit vaccines against infectious diseases or cancer.     

Effect of Size on the Biodistribution and Blood Clearance of Etoposide-Loaded PLGA Nanoparticles

Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm ((99m)Tc-Eto-PLGA NP(105)) and 160 nm ((99m)Tc-Eto-PLGA NP(160)) on biodistribution and blood clearance were studied after intravenous administration of the radiolabeled formulations and compared to that of free drug ((99m)Tc-Eto). It was found that etoposide-loaded PLGA NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA NPs of size 160 nm and pure drug. Moreover, the pure drug ((99m)Tc-Eto) did not cross the blood-brain barrier, whereas (99m)Tc-Eto-PLGA NP(105) showed relatively high concentrations of 0.58% of injected dose in brain in 1 h (8-fold higher), 0.6% in 4 h (20-fold higher) and 0.22% in 24 h (10-fold higher) than the concentration of (99m)Tc-Eto-PLGA NP(160). In bone, concentration of (99m)Tc-Eto-PLGA NP(105) was about 7.2 times higher than the concentration of (99m)Tc-Eto in 24 h. The study concludes that NPs of size ～100 nm can be used for long-term circulation without the need for surface modification. Such NPs could be exploited for use in leukemia therapy for providing sustained release of etoposide by long-term circulation. LAY ABSTRACT: Approaches used to avoid uptake of the injected particles by the reticuloendothelial system include modification of the particle properties such as surface charge and particle size. In the present study the effect of mean particle size of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) of sizes 105 nm and 160 nm on biodistribution studies after intravenous administration in mice and blood clearance studies after intravenous administration in rats was studied. It was found that etoposide-loaded PLGA-NPs of size 105 nm were present in the blood at higher concentrations up to 24 h and were able to reduce their uptake by the reticuloendothelial system as compared to that of etoposide-loaded PLGA-NP of size 160 nm and pure drug. Moreover, the NPs of size 105 nm had greater uptake in bone and brain, in which concentration of free drug and NPs of size 160 nm was negligible. The study concludes that NPs of size ～100 nm can be used for long-term circulation without the need for surface modification.     

Targeted delivery of monoclonal antibody conjugated docetaxel loaded PLGA nanoparticles into EGFR overexpressed lung tumour cells

The aim of this study was to develop anti-EGFR antibody conjugated poly(lactide-co-glycolide) nanoparticles (NPs) to target epidermal growth factor receptor, highly expressed on non-small cell lung cancer cells to improve cytotoxicity and site specificity. Cetuximab was conjugated to docetaxel (DTX) loaded PLGA NPs by known EDC/NHS chemistry and characterised for size, zeta potential, conjugation efficiency and the results were 128.4?±?3.6?nm, –31.0?±?0.8?mV, and 39.77?±?3.4%, respectively. In vitro release study demonstrated sustained release of drug from NPs with 25% release at pH 5.5 after 48?h. In vitro cytotoxicity studies demonstrated higher anti-proliferative activity of NPs than unconjugated NPs. Cell cycle analysis and apoptosis study were performed to evaluate extent of cell arrest at different phases and apoptotic potential for the formulations, respectively. In vivo efficacy study showed significant reduction in tumour growth and so antibody conjugated NPs present a promising active targeting carrier for tumour selective therapeutic treatment.     

无稳定剂修饰的汉防己甲素PLGA纳米粒制备及体外评价

目的:制备无稳定剂修饰的汉防己甲素PLGA纳米粒,研究其理化性质及细胞毒和细胞摄取特性。方法:以聚乳酸-羟基醋酸共聚物(PLGA)为载体材料,采用无稳定剂修饰的纳米沉淀法制备汉防己甲素纳米粒;通过单因素试验考察不同制备工艺对纳米粒理化性质的影响;通过载药量、包封率、累积释药量等指标考察其载药特性;采用MTT比色法检测其对人肺腺癌细胞株A549的细胞毒性;采用共聚焦显微镜技术考察其细胞摄取特性。结果:无稳定剂修饰的汉防己甲素PLGA纳米粒平均粒径169.3 nm,与有稳定剂的汉防己甲素PLGA纳米粒相比外观无明显改变。在一定范围内,随着PLGA用量的增加,纳米粒的粒径呈上升趋势;随着投药量的增加,纳米粒的载药量显著增加,包封率下降。在pH7.4的释放介质中,纳米粒释慢释药,96 h累积释药率60.44%。细胞毒试验显示,当培养时间为8 h时,汉防己甲素组的细胞毒性大于汉防己甲素纳米粒组;当培养时间延长至24 h时,汉防己甲素纳米粒组的细胞活性明显低于纯药物组;高剂量的空白纳米粒组始终表现较低的细胞毒性。激光共聚焦电镜断层扫描显示汉防己甲素纳米粒能够较好的被细胞摄取。结论:制备的无稳定剂修饰的汉防己甲素PLGA纳米粒大小均一,包封率高,体外释药表现出较好的缓释效果,易被细胞摄取,对A549细胞的增殖有明显的抑制作用。     

Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers

Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood–brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200?nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The P-gp ATPase assay suggested that the NP were not substrate for P-gp and would not be effluxed by P-gp present in the BBB. The in vitro release profile of the NP exhibited no initial burst release and showed sustained drug release. The proposed coated NP showed significantly higher cytotoxicity in RG2 cells compared with uncoated NP (p?≤?0.05). Tubulin immunofluorescent study showed higher cell death by the NP due to increased microtubule stabilization. In vivo brain uptake study in mice showed higher brain uptake of the NP containing coumarin-6 compared with solution. The proposed brain-targeted NP delivery of paclitaxel could be an effective treatment for the brain cancers.     

Formulation and optimization of celecoxib-loaded PLGA nanoparticles by the Taguchi design and their in vitro cytotoxicity for lung cancer therapy

Abstract

The objective of the present study was to develop, evaluate and optimize a polymeric nanoparticle (NP) system containing Cxb for pulmonary delivery of Cxb in the treatment of lung cancer. NPs were prepared by the emulsion solvent diffusion and evaporation method using poly(D, L lactideglycolide) (PLGA). The size of NPs ranged from 153 to 192?nm and was affected by PLGA content, surfactant concentration and organic phase volume. Zeta potential of NPs (?4.5 to ?8.6?mV) was more affected by PLGA content and organic phase volume. PLGA content was also the most effective factor on the entrapment efficiency and release rate of Cxb from NPs. The optimum formulation which obtained with 5?mg Cxb, 25?mg PLGA, 0.5% surfactant, 2.5% organic volume and 15?000?rpm showed release of Cxb within 30?h. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass medium aerodynamic diameter, geometric standard deviation of 70.3%, 1.46% and 3.38%, respectively. Our results provide evidence for the potential of PLGA NPs for delivery of Cxb through inhalation as means to alleviate the cardiovascular risk of Cxb administration.     

Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention

We studied the molecular mechanism of greater efficacy of paclitaxel-loaded nanoparticles (Tx-NPs) following conjugation to transferrin (Tf) ligand in breast cancer cell line. NPs were formulated using biodegradable polymer, poly(lactic-co-glycolide) (PLGA), with encapsulated Tx and conjugated to Tf ligand via an epoxy linker. Tf-conjugated NPs demonstrated greater and sustained antiproliferative activity of the drug in dose- and time-dependent studies compared to that with drug in solution or unconjugated NPs in MCF-7 and MCF-7/Adr cells. The mechanism of greater antiproliferative activity of the drug with conjugated NPs was determined to be due to their greater cellular uptake and reduced exocytosis compared to that of unconjugated NPs, thus leading to higher and sustained intracellular drug levels. The increase in antiproliferative activity of the drug with incubation time in MCF-7/Adr cells with Tf-conjugated NPs suggests that the drug resistance can be overcome by sustaining intracellular drug retention. The intracellular disposition characteristics of Tf-conjugated NPs following their cellular uptake via Tf receptors could have been different from that of unconjugated NPs via nonspecific endocytic pathway, thus influencing the NP uptake, their intracellular retention, and hence the therapeutic efficacy of the encapsulated drug.     

Nanotechnology-based drug delivery of ropinirole for Parkinson’s disease

A new drug delivery system is developed for ropinirole (RP) for the treatment of Parkinson’s disease (PD) consisting of biodegradable poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). The formulation selected was prepared with 8?mg RP and 50?mg PLGA 502. This formulation exhibited mean encapsulation efficiency of 74.8?±?8.2%, mean particle size lower than 155?nm, the zeta potential of ?14.25?±?0.43?mV and zero-order in vitro release of RP (14.13?±?0.17?μg/h/10?mg NPs) for 5?d. Daily doses of the neurotoxin rotenone (2?mg/kg) given i.p. to male Wistar rats induced neuronal and behavioral changes similar to those of PD. Once neurodegeneration was established (15?d) animals received RP in saline (1?mg/kg/d for 35?d) or encapsulated within PLGA NPs (amount of NPs equivalent to 1?mg/kg/d RP every 3 d for 35?d). Brain histology and immunochemistry (Nissl-staining, glial fibrillary acidic protein and tyrosine hydroxylase immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that RP-loaded PLGA NPs were able to revert PD-like symptoms of neurodegeneration in the animal model assayed.     

Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood–brain barrier

Many studies showed that transferrin increases brain delivery of nanoparticles (NPs) in vivo, however the mechanisms implied in their brain uptake are not yet clearly elucidated. In this study we evaluated the endocytosis of PLGA NPs coated with transferrin on an in vitro model of the blood–brain barrier (BBB) made of a co-culture of brain endothelial cells and astrocytes. PLGA NPs were prepared using DiI as a fluorescent marker and coated with Tween^® 20, BSA and transferrin (Tf). Blank and BSA-NPs served as controls. The cellular toxicity on BBB of the different samples was evaluated following tight junction aperture and due to high toxicity NPs prepared with Tween^® 20 were discarded. The size of the NPs prepared by the solvent diffusion method, varied from 63 to 90 nm depending on DiI incorporation and surface coating. Proteins adsorption on the surface of the NPs was found to be stable for at least 12 days at 37 °C. Contrary to Blank or BSA-NPs, Tf-NPs were found to be highly adsorbed by the cells and endocytosed using an energy-dependent process. Studies in presence of inhibitors suggest that Tf-NPs interact with the cells in a specific manner and enter the cells via the caveolae pathway.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8-1?μm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In?vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

Versatility of biodegradable poly(D,L-lactic-co-glycolic acid) microspheres for plasmid DNA delivery.

In this study, we have optimized different formulations of DNA encapsulated into PLGA microspheres by correlating the protocol of preparation and the molecular weight and composition of the polymer, with the main characteristics of these systems in order to design an efficient non-viral gene delivery vector. For that, we prepared poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles with an optimized water-oil-water double emulsion process, by using several types of polymers (RG502, RG503, RG504, RG502H and RG752), and characterized in terms of size, zeta potential, encapsulation efficiency (EE%), morphology, DNA conformation, release kinetics, plasmid integrity and erosion. The size of the particles ranged between 0.7 and 5.7 microm depending on the protocol of formulation and the molecular mass of the polymer used. The microspheres prepared by using in their formulation polymers of high molecular weight (RG503 and RG504) were bigger in size than in the case of using a lower molecular weight polymer (RG502). The EE (%) of plasmid DNA increased with increasing the molecular mass of the polymer and by using the most hydrophilic polymer RG502H, which contains terminal acidic groups in its structure. The plasmid could be encapsulated without compromising its structural and functional integrity. Also a protective effect of PLGA on endonuclease digestion is observed. Plasmid DNA release from microspheres composed of low molecular weight or hydrophilic polymers, like RG502H, was faster than from particles containing high molecular weight or hydrophobic polymers. These PLGA microspheres could be an alternative to the viral vectors used in gene therapy, given that may be used to deliver genes and other bioactive molecules, either very rapidly or in a controlled manner.     

Paclitaxel-loaded polyester nanoparticles prepared by spray-drying technology: in vitro bioactivity evaluation

Paclitaxel (PTX), an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles (NPs) of poly(lactide-co-glycolide) (PLGA) and poly(ε-caprolactone) (PCL) polymers using the spray-drying technique. Morphology, size distribution, drug encapsulation efficiency, thermal degradation and drug release were characterized. MCF7 cells were employed to evaluate the efficacy of the systems on cell cycle and cytotoxicity. The particle size was in the range 0.8–1?µm. The incorporation efficiency of PTX was more than 80% in all NPs obtained. In vitro drug release took place during 35 days, and drug release rates were in the order PCL?>?PLGA 50:50?>?PLGA 75:25. Unloaded NPs showed to be cytocompatible at MCF7 cells. PTX-loaded NPs demonstrated the release of the drug block cells in the G2/M phase. All PTX-loaded formulations showed their efficacy in killing MCF7 cells, mainly PTX-loaded PLGA 50:50 and PLGA 75:25 that cause a decrease in cell viability lower than 20%.     

Local drug delivery using poly(lactic-co-glycolic acid) nanoparticles in thermosensitive gels for inner ear disease treatment

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of −18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.     

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano‐vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification–solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl‐lactic‐co‐glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP‐PLGA‐NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP‐PLGA‐NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma‐aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme‐linked immunosorbent assay. The maximal electroshock‐induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP‐loaded NPs. The prepared ZP‐PLGA NPs were negatively charged spherical particles with an average size of 120–300 nm. Optimized ZP‐PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42‐fold augmentation in oral drug bioavailability in comparison to ZP‐marketed products. Moreover, parenteral administration of ZP‐NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP‐PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.     

Bioavailability enhancement,Caco-2 cells uptake and intestinal transport of orally administered lopinavir-loaded PLGA nanoparticles

Nanoparticles (NPs) can be absorbed via M cells of Peyer’s patches after oral delivery leading to passive lymphatic targeting followed by systemic drug delivery. Hence, the study was aimed to formulate PLGA NPs of lopinavir. The NPs were prepared by nanoprecipitation, optimized by 3³ factorial design and characterized by TEM, DSC, FTIR studies and safety was assessed by MTT assay. In vivo pharmacokinetic studies were performed in rats. The NPs were discrete spherical structures having particle size of 142.1?±?2.13?nm and entrapment of 93.03?±?1.27%. There was absence of drug-polymer interaction. Confocal images revealed the penetration and absorption of coumarin-loaded NPs in Caco-2 cells and intestine after oral delivery. There was 3.04 folds permeability and 13.9 folds bioavailability enhancement from NPs. The NPs can be promising delivery system for antiretroviral drug by delivering the drug to lymph (major HIV reservoir site) via direct absorption through intestine before reaching systemic circulation.     

Methyl trypsin loaded poly(D,L-lactide-coglycolide) nanoparticles for contact lens care

The need of an enzymatic cleaner for soft contact lens care with an improved ocular safety and stability profile led us to evaluate the use of nanoparticles (NPs) of poly(D,L-lactide-coglycolide) (PLGA) and methyl trypsin (MT). NPs were prepared by double emulsion–solvent evaporation technique. A factorial design was performed to select the lactic acid proportion in the copolymer and conditions of the second sonication. The increment in proportion of lactic acid provided higher particle size results. When the time of second sonication was decreased, the entrapment efficiency (EE) increased. PLGA 50:50 NPs were chosen for further development since PLGA 50:50H NPs settled fast with different particle size in the sediment and PLGA 75:25 NPs led to form aggregates. The addition of glycerol to the NPs provided the highest EE of MT (>90%) while the addition of Tetronic® 1304 promoted the fast release of enzyme initially and decreased the zeta potential (ζ) up to neutral values after gamma irradiation. NPs are expected to be effective as a lens care cleaner after 3 days or even longer with a very low quantity of enzyme released. Formulations showed an acceptable irritation ocular tolerance after in vitro HET-CAM test and in vivo Draize test. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1414–1426, 2010     

Long circulating nanoparticles of etoposide using PLGA‐MPEG and PLGA‐pluronic block copolymers: characterization,drug‐release,blood‐clearance,and biodistribution studies

The anti‐leukemic drug, etoposide (ETO), has variable oral bioavailability ranging from 24–74% with a short terminal half‐life of 1.5 h i.v. necessitating continuous infusion for 24–34 h for the treatment of leukemia. In the present study, etoposide‐loaded PLGA‐based surface‐modified nanoparticles (NPs) with long circulation were designed as an alternative to continuous i.v. administration. PLGA‐mPEG and PLGA‐PLURONIC copolymers were synthesised and used to prepared ETO‐loaded NPs by high‐pressure homogenization. The mean particle size of ETO‐loaded PLGA‐MPEG nanoparticles was 94.02±3.4 nm, with an Entrapment Efficiency (EE) of 71.2% and zeta potential value of −6.9±1.3 mV. ETO‐loaded PLGA‐pluronic nanoparticles had a mean particle size of 148.0±2.1 nm, an EE of 73.12±2.7%, and zeta potential value of −21.5±1.6 mV. In vitro release of the pure drug was complete within 4 h, but was sustained up to 7 days from PLGA‐mPEG nanoparticles and for 5 days from PLGA‐pluronic nanoparticles. Release was first order and followed non‐Fickian diffusion kinetics in both instances. ETO and ETO‐loaded PLGA nanoparticles labeled with ^99mTc were used in blood clearance studies in rats where the two coated NPs, ^99mTc‐ ETO‐PLGA‐PLU NP and ^99mTc‐ ETO‐PLGA‐mPEG NP, were found to be available in higher concentrations in the circulation as compared to the pure drug. Biodistribution studies in mice showed that ETO‐loaded PLGA‐MPEG NP and PLGA‐PLURONIC NP had reduced uptake by the RES due to their steric barrier properties and were present in the circulation for a longer time. Moreover, the NPs had greater uptake in bone and brain where concentration of the free drug, ETO, was negligible. Drug delivered from these NPs could result in a single i.v. injection that would release the drug for a number of days, which would be potentially beneficial and in better control of leukemia therapy. Drug Dev Res 71: 228–239, 2010. © 2010 Wiley‐Liss, Inc.