Performance tuning of particle engineered mannitol in dry powder inhalation formulations.

Typically, smooth lactose particles are used as carrier in dry powder formulations for inhalation. Two classical approaches to improve their aerodynamic behaviour are the addition of fines (milled lactose) or magnesium stearate (MgSt). Mannitol (Parteck® M DPI) as an alternative carrier was used in this study. It has an irregular particle size distribution and a large and rough surface. This could be challenging for the detachment of micronised drug upon inhalation and it is unclear whether classic strategies for the optimisation of aerodynamic performance can be applied. In contrast, its rough surface could be an advantage in terms of drug load. To address these questions, the mannitol carrier was blended with two different drugs using various concentrations up to 50%. Self-produced mannitol fines and MgSt in different amounts and in combination were added. Blends were investigated regarding their in vitro aerodynamic performance, dosing behaviour and powder rheology. An addition of up to 30% drug load was possible while retaining good flowability and constant dosing behaviour. Despite the rough and indented carrier surface of the mannitol carrier, the addition of fines or MgSt increased the inhalable fraction, but higher concentrations of fines, as used for lactose blends, were necessary.

Particle engineered mannitol for carrier-based inhalation - A serious alternative?

In dry powder inhalation (DPI), larger carrier particles, typically lactose, are blended with micronised active pharmaceutical ingredient (API) particles to improve handling, processability and inhalable fraction. Alternative carrier materials were researched for years, but did not enter the market yet. In this study, a common lactose carrier for DPI formulations and a spray granulated mannitol carrier were compared to evaluate if the particle engineered mannitol can be considered a serious alternative. Blends with five different API concentrations (0.1 to 4%) were prepared with two APIs. Physical carrier and blend characterisation regarding particle size, morphology, density, shear cell testing and dosing behaviour were performed. Aerodynamic assessment was done using two different inhaler devices (one capsule-based inhaler and one reservoir-based inhaler). In addition, the influence of different flow rates was examined. Results indicated that uniform dosing in metered mass and delivered dose over this API concentration range was achieved due to good flowability of the blends. Furthermore, linear dose delivery could be seen over the added API concentrations. Impaction analysis showed that the respirable fractions of mannitol blends were comparable (for salbutamol sulphate blends) or higher (for budesonide blends) than with a standard lactose carrier.

Content of phenolic compounds and mannitol in olive leaves extracts from six Spanish cultivars: Extraction with the Soxhlet method and pressurized liquids.

Olive leaves are considered a promising source of bioactives such as phenolic compounds and mannitol. The extraction of high added value products is an issue of great interest and importance from the point of view of their exploitation. However, the content of these compounds can differ between cultivars and extraction methods. In this work, six olive leaves cultivars, including three wild cultivars, and two extraction processes (an innovative and alternative technique, pressurized liquid extraction, and a conventional Soxhlet extraction) were evaluated and compared towards the selective recovery of bioactive compounds. The wild cultivars showed the highest content of phenolic and flavonoid compounds, being oleuropein the compound present in higher amount. Findings also revealed that the highest mannitol content in the extracts was observed with the commercial cultivars, specifically in Arbequina. It is thus possible to decide which cultivars to use in order to obtain the highest yield of each bioproduct.

GABAB receptor ligand-directed trimethyl chitosan/tripolyphosphate nanoparticles and their pMDI formulation for survivin siRNA pulmonary delivery.

The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABAB receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABAB receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABAB receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39±2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment.

The traditional uses, phytochemistry, and pharmacology of Atractylodes macrocephala Koidz.: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes macrocephala Koidz. (called Baizhu in China) is a medicinal plant that has long been used as a tonic agent in various ethno-medical systems in East Asia, especially in China, for the treatment of gastrointestinal dysfunction, cancer, osteoporosis, obesity, and fetal irritability. AIM OF THE REVIEW: This review aims to provide a systematic summary on the botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of A. macrocephala to explore the future therapeutic potential and scientific potential of this plant. MATERIALS AND METHODS: A literature search was performed on A. macrocephala using scientific databases including Web of Science, Google Scholar, Baidu Scholar, Springer, PubMed, SciFinder, and ScienceDirect. Information was also collected from classic books of Chinese herbal medicine, Ph.D. and M.Sc. dissertations, unpublished materials, and local conference papers on toxicology. Plant taxonomy was confirmed to the database "The Plant List" (www.theplantlist.org). RESULTS: More than 79 chemical compounds have been isolated from A. macrocephala, including sesquiterpenoids, triterpenoids, polyacetylenes, coumarins, phenylpropanoids, flavonoids and flavonoid glycosides, steroids, benzoquinones, and polysaccharides. Crude extracts and pure compounds of A. macrocephala are used to treat gastrointestinal hypofunction, cancer, arthritis, osteoporosis, splenic asthenia, abnormal fetal movement, Alzheimer disease, and obesity. These extracts have various pharmacological effects, including anti-tumor activity, anti-inflammatory activity, anti-aging activity, anti-oxidative activity, anti-osteoporotic activity, neuroprotective activity, and immunomodulatory activity, as well as improving gastrointestinal function and gonadal hormone regulation. CONCLUSIONS: A. macrocephala is a valuable traditional Chinese medicinal herb with multiple pharmacological activities. Pharmacological investigations support the traditional use of A. macrocephala, and may validate the folk medicinal use of A. macrocephala to treat many chronic diseases. The available literature shows that much of the activity of A. macrocephala can be attributed to sesquiterpenoids, polysaccharides and polyacetylenes. However, there is a need to further understand the molecular mechanisms and the structure-function relationship of these constituents, as well as their potential synergistic and antagonistic effects. Further research on the comprehensive evaluation of medicinal quality, the understanding of multi-target network pharmacology of A. macrocephala, as well as its long-term in vivo toxicity and clinical efficacy is recommended.

Uptake and desorption of hydrophilic compounds from human stratum corneum.

Small, polar compounds, both ionic and uncharged, partition into human stratum corneum immersed in aqueous solutions to an extent comparable to the water volume fraction of the tissue, then desorb in two phases. The fast phase has a time constant on the order of a few minutes, whereas the slow phase occurs over many hours. A physical model for this behavior involving a combination of tranverse diffusion through the tissue and lateral diffusion and exchange with skin appendages is presented. This concept is probed using excised human stratum corneum exposed to aqueous solutions of radiolabeled sodium chloride, tetraethyl ammonium bromide and mannitol, plus previously published data on six other compounds of varying molecular size and polarity. The fast phase desorption process becomes unimportant for lipophilic compounds. Slow phase desorption rates are size-selective, with larger species desorbing much more slowly than smaller ones. Interpreting the size-selectivity in terms of smooth cylindrical pores using the centerline approximation leads to an optimum pore radius of about 8-12Å, depending on the model chosen.

Proniosomal powders of natural canthaxanthin: Preparation and characterization.

In this study, canthaxanthin (CTX) was produced by Dietzia natronolimnaea HS-1 using beetroot molasses as substrate and used for encapsulation in proniosome powders after extraction, with the aim of improving its stability. Proniosome powders were prepared with an equimolar ratio of span 60/cholesterol and four different carriers, namely maltodextrin, mannitol, lactose and pullulan. The properties of these formulations as both proniosomal powders and resulted niosomal dispersions were evaluated. The type of carriers had significant effects on the micrometric properties of proniosome powders which were further confirmed by the results of SEM analysis. Although light and high temperatures affected the stability of CTX drastically, but encapsulation in proniosomes retarded its degradation. Among these samples, mannitol based proniosome powder (MAPP) produced small vesicles (mean diameter=175±3nmand polydispersity index=0.28±0.02) with the highest entrapment efficiency (74.1±2.7%). MAPP provided a promising formulation to increase CTX stability especially upon storage at high temperatures (45°C).

Diversity selection, screening and quantitative structure-activity relationships of osmolyte-like additive effects on the thermal stability of a monoclonal antibody.

Solvents used for therapeutic proteins in downstream processing and in formulations often contain stabilizing additives that inhibit denaturation and aggregation. Such additives are mostly selected based on their positive effect on thermal stability of the protein, and are often derived from naturally occuring osmolytes. To better understand the structural basis underlying the effect of additives, we selected a diverse library of compounds comprising 79 compounds of the polyol, amino acid and methylamine chemical classes and determined the effect of each compound on thermal stability of a monoclonal antibody as a function of compound concentration. Thermal stabilization of the antibody was influenced by solution pH. Quantitative structure-activity relationships (QSAR) were derived by partial least squares regression for individual compound classes and globally. The global model suggests that ligands with a phenyl ring will decrease the Tm, while highly soluble, polar compounds with at least two hydrogen bond donors will increase the Tm. This approach may be beneficial for further studies on the influence of other solution conditions like ionic strength and buffer species on additive-mediated protein stabilization.

Effect of mitochondrial apoptotic activation through the mitochondrial membrane permeability transition pore on yak meat tenderness during postmortem aging.

The effect of membrane permeability transition pore dependent mitochondrial apoptotic activation on yak meat tenderness was investigated. Results indicate that MPTP opening increased significantly and the mitochondrial membrane potential decreased markedly in the early aging process (P<0.05). Cytochrome c was released from the mitochondria to the cytoplasm via the MPTP in the early period. Meanwhile, the activation of procaspase-9 occurred earlier than that of procaspase-3. Cyclosporin A suppressed the MPTP opening, depolarization of the mitochondrial membrane potential, activities of caspase-9 and caspase-3, apoptosis rate, myofibril fragmentation index, reactive oxygen species generation, and Ca2+ levels. These results demonstrated that MPTP mediated the release of cytochrome c in the mitochondrial apoptotic pathway. Furthermore, yak meat tenderness was improved by mitochondrial apoptotic pathway during aging. MPTP opening may be influenced by the ROS generation and Ca2+ overloading in yak meat during postmortem aging.

Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties.

Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1B to F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1B were rapidly distributed from the lungs (t1/2i 2.6 and 5.0min). F2B was eliminated in ∼1h (t1/2i 9.0min). F3B lung retention was sustained for ∼7h (t1/2i 59.9min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1B and F2B. Total blood tmax were higher and AUC and Cmax lower using the pulmonary route vs. IV. Kidney Cmax was reduced 6-, 2- and 3-fold for F1B, F2B and F3B. AUC in kidneys were 2- to 3-fold lower for F1B and F2Bvs. IV but comparable for IV vs. F3B, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties.

QbD based development of proliposome of lopinavir for improved oral bioavailability.

Aim of present work was to apply quality by design (QbD) principles for the development of proliposome of poorly soluble lopinavir (LPV). The patient-centric quality target product profile (QTPP) was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies were carried out to identify the probable risks affecting the CQAs of the product. On the basis of preliminary study, lipid:drug ratio and amount of carrier were selected as critical material attributes (CMAs) and were optimized by face centered central composite design. Liposome vesicle size, drug entrapment efficiency and % drug release after 60min were selected as CQAs and mathematical relationship between CQAs and CMAs was derived using multiple linear regression analysis. Optimum composition of CMAs, identified using numerical optimization and desirability function, demonstrated excellent entrapment efficiency (>90%), drug release characteristics (>95% in 60min) and had vesicle size of 659.7±23.1nm. Solid state characterization studies (Differential Scanning Calorimetry, scanning electron microscopy and X-ray diffraction) were performed for optimized proliposome, suggested transformation of crystalline to amorphous form. Oral bioavailability study in Wistar rats revealed that LPV proliposome exhibited 2.24 and 1.16 fold higher bioavailability than pure LPV and available commercial formulation of LPV/RTV (lopinavir+ritonavir), respectively. Stability study of the optimized LPV loaded proliposome was performed as per ICH guideline and was found to be stable for period of 6months. Overall results of the study indicate that the proliposome offers advantages of enhanced oral bioavailability for poorly soluble LPV.

Prevalence and molecular characterization of Clostridium difficile isolates from a pig slaughterhouse, pork, and humans in Taiwan.

Clostridium difficile causes antibiotic-associated diarrhea in both humans and animals. The ribotype 078, predominant in food animals, is associated with community-acquired C. difficile infection, and C. difficile is suggested to be a foodborne pathogen. Recently, the C. difficile ribotype 078 lineage emerged in patients and pigs in Taiwan. This study aimed to investigate the prevalence and molecular characterization of C. difficile isolated from a pig slaughterhouse, retail meat, ready-to-eat meals, and humans in Taiwan. We collected samples from one slaughterhouse (n=422), 29 retail markets (raw pork, n=62; ready-to-eat pork, n=65), and one hospital (non-diarrheal humans, stool, n=317) in 2015. The isolated C. difficile were subjected to ribotyping and multilocus variable-number tandem-repeat analysis (MLVA). In the slaughterhouse, the isolation rate from carcasses was high (23%, 21/92) and ribotype 126 dominated. Scalding water was found to have C. difficile contamination (44%, 4/9), and two of the seven isolates were ribotype 126. The isolation rates from raw pork and ready-to-eat pork were between 20% and 29%. Ribotypes 126, 127, and 014 were found in raw pork, whereas ribotype 078 was not identified in this study. Eight isolates-seven non-toxigenic isolates and one ribotype 017-were found in non-diarrheal human samples. Notably, MLVA showed that ribotype 126 isolates from the slaughterhouse, pig stool, colons, carcasses, and scalding water were closely genetically related, indicating serious risk for cross-contamination. However, the genetic evidence of foodborne transmission from carcasses to food and humans is still lacking.

Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol.

Mannitol is a pharmaceutical excipient that is receiving increased popularity in solid dosage forms. The aim of this study was to provide comparative evaluation on the effect of mannitol concentration on the physicochemical, mechanical, and pharmaceutical properties of lyophilised mannitol. The results showed that the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol powders are strong functions of mannitol concentration. By decreasing mannitol concentration, the true density, bulk density, cohesivity, flowability, netcharge-to-mass ratio, and relative degree of crystallinity of LM were decreased, whereas the breakability, size distribution, and size homogeneity of lyophilised mannitol particles were increased. The mechanical properties of lyophilised mannitol tablets improved with decreasing mannitol concentration. The use of lyophilised mannitol has profoundly improved the dissolution rate of indomethacin from tablets in comparison to commercial mannitol. This improvement exhibited an increasing trend with decreasing mannitol concentration. In conclusion, mannitols lyophilised from lower concentrations are more desirable in tableting than mannitols from higher concentrations due to their better mechanical and dissolution properties.

Effect of different polyol-based plasticizers on thermal properties of polyvinyl alcohol:starch blends.

A series of gelatinized polyvinyl alcohol (PVA):starch blends were prepared with various polyol-based plasticizers in 5 wt%, 15 wt% and 25 wt% ratios via solution casting method. The obtained films were analyzed by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Remarkable changes have been observed in glass-transition temperature (Tg) and thermal stability of the samples containing varying concentrations of different plasticizers and they have been discussed in detail with respect to the conducted thermal and chemical analyses. The observed order of Tg point depression of the samples containing 15 wt% plasticizer is 1,4-butanediol - 1,2,6-hexanetriol--pentaerythriyol--xylitol--mannitol, which is similar to the sequence of the thermal stability changes of the samples.

Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy.

Despite the direct access to the lung offered by the inhalation route, drug penetration into lung tumors could remain an important issue. In this study, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD) micelles were developed as an effective pulmonary drug delivery system to reach and penetrate lung tumors and cancer cells. The F-PEG-HMD micelles were able to enter HeLa and M109-HiFR, two folate receptor-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. Paclitaxel-loaded F-PEG-HMD micelles characterized in PBS by a Z-average diameter of ∼50 nm and a zeta potential of ∼-4 mV were prepared with an encapsulation efficiency of ∼100%. The loaded micelles reduced HeLa and M109-HiFR cell growth, with half maximal inhibitory concentrations of 37 and 150 nM, respectively. Dry powders embedding the paclitaxel-loaded F-PEG-HMD micelles were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the micelles in physiological buffer. A polymeric micelle-based dry powder without paclitaxel was well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1ß, IL-6, and TNF-α concentrations in bronchoalveolar lavage fluids.

Solid Lipid Nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment-A Design of Experiments approach to investigate the influence of pre-freezing conditions on the powder respirability.

For direct intramacrophagic antitubercular therapy, pulmonary administration through Dry Powder Inhaler (DPI) devices is a reasonable option. For the achievement of efficacious aerosolisation, rifampicin-loaded Solid Lipid Nanoparticle assemblies (SLNas) were developed using the melt emulsifying technique followed by freeze-drying. Indeed, this drying method can cause freezing or drying stresses compromising powder respirability. It is the aim of this research to offer novel information regarding pre-freezing variables. These included type and concentration of cryoprotectants, pre-freezing temperature, and nanoparticle concentration in the suspension. In particular, the effects of such variables were observed at two main levels. First of all, on SLNas characteristics - i.e., size, polydispersity index, zeta-potential, circularity, density, and drug loading. Secondly, on powder respirability, taking into account aerodynamic diameter, emitted dose, and respirable fraction. Considering the complexity of the factors involved in a successful respirable powder, a Design of Experiments (DoE) approach was adopted as a statistical tool for evaluating the effect of pre-freezing conditions. Interestingly, the most favourable impact on powder respirability was exerted by quick-freezing combined with a certain grade of sample dilution before the pre-freezing step without the use of cryoprotectants. In such conditions, a very high SLNas respirable fraction (>50%) was achieved, along with acceptable yields in the final dry powder as well as a reduction of powder mass to be introduced into DPI capsules with benefits in terms of administered drug dose feasibility.

Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy.

The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.

Paeoniflorin inhibits high glucose-induced macrophage activation through TLR2-dependent signal pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin(PF), extracted from the root peeled of Paeonia lactiflora Pall(Family: Ranunculaceae), has therapeutic potential in many animal models of inflammatory diseases. AIM OF THE STUDY: Although the anti-inflammatory efficacy of PF has been well illustrated in several animal models, whether it could attenuate diabetic nephropathy and detailed mechanisms are still obscure. Till now, accumulating evidence has proposed the pivotal role of toll-like receptors (TLRs) in renal inflammation in diabetic patients. In this setting, the current study aimed to investigate the effects and underlying mechanism of PF on high glucose-induced activation of toll like-receptor 2 (TLR2) signaling in macrophages. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDM) were isolated from male Tlr2tm1kir (TLR2-/-) mice and wild-type littermates (C57BL/6JWT). The level of TLR2 and activation of downstream signaling were evaluated in response to 30mmol/L high glucose (HG)-containing medium. Macrophages behaviors, which include cell viability, migration and inflammatory cytokines production, were also determined. RESULTS: PF suppressed HG-induced production of TLR2, activation of downstream signaling and synthesis of inducible nitric oxide synthase (iNOS). PF could further inhibit MyD88-dependent pathway in HG-induced models in which TLR2 was knocked out. Moreover, deletion of TLR2 inhibited the HG-induced activation of MyD88-dependent pathway, but not TIR domain containing adapter inducing interferon-ß (Trif) signal pathway in BMDMs. As HG stimulation polarizes macrophages into M1 phenotype, treatment of PF or knockout of TLR2 significantly reduces M1 markers on the membrane of macrophages. Additionally, levels of inflammatory cytokines and iNOS were remarkably reduced in response to PF or TLR2 deficiency. CONCLUSION: Collectively, these data demonstrated that HG activated macrophages primarily through TLR2-dependent mechanisms which aggravated the severity of renal inflammation and eventually contributed to DN. Additionally, PF might be applied as a potential therapeutic agent in the battle against progressive DN.

Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS.

In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS.

Investigation of imatinib loaded surface decorated biodegradable nanocarriers against glioblastoma cell lines: Intracellular uptake and cytotoxicity studies.

Overexpression of P-glycoprotein (P-gp) efflux transporter in glioma cells thwarts the build-up of therapeutic concentration of drugs usually resulting into poor therapeutic outcome. To surmount aforesaid challenge, Imatinib (IMM) loaded Poly-lactide-co-glycolic acid nanoparticles (IMM-PLGA-NPs) were developed and optimized by Box Behnken Design as a new treatment stratagem in malignant glioma. Optimized NPs were functionalized with Pluronic(®) P84, P-gp inhibitor (IMM-PLGA-P84-NPs) which showed size, PDI, zeta potential, drug loading, 182.63±13.56nm, 0.196±0.021, -15.2±1.49mV, 40.63±2.04µg/mg, respectively. Intracellular uptake study conducted on A172, U251MG and C6 glioma cells demonstrated significantly high uptake of IMM through NPs when compared with IMM solution (IMM-S), p<0.001. IMM-PLGA-P84-NPs showed better uptake in P-gp expressing cell line (U251MG and C6) while uncoated NPs showed higher uptake in non-P-gp expressing cell line (A-172). Cytotoxicity studies demonstrated significantly low IC50 for both IMM-PLGA-NPs and IMM-PLGA-P84-NPs when compared with IC50 of IMM-S. IMM-PLGA-P84-NPs showed a significantly low IC50 against P-gp overexpressing cell lines when compared with IC50 of IMM-PLGA-NPs. In contrary, IMM-PLGA-NPs showed lower IC50 against non P-gp expressing cell line. This study demonstrated the feasibility of targeting surface decorated NPs to multidrug resistant gliomas. However, to address its clinical utility extensive in vivo studies are required.