Curcumin-polymeric nanoparticles against colon-26 tumor-bearing mice: cytotoxicity, pharmacokinetic and anticancer efficacy studies.

CONTEXT: Curcumin (CUR), can inhibit proliferation and induce apoptosis of tumor cells, its extreme insolubility and limited bioavailability restricted its clinical application. OBJECTIVE: An innovative polymeric nanoparticle of CUR has been developed to enhance the bioavailability and anti-cancer efficacy of CUR, in vitro and in vivo. MATERIALS AND METHODS: Cationic copolymer Eudragit E 100 was selected as carrier, which can enhance properties of poor bioavailable chemotherapeutic drugs (CUR). The CUR-loaded Eudragit E 100 nanoparticles (CENPs) were prepared by emulsification-diffusion-evaporation method. The in vitro cytotoxicity study of CENPs was carried out using sulphorhodamine B assay. Pharmacokinetic and anti-cancer efficacy of CENPs was investigated in Wister rats as well as colon-26 tumor-bearing mice after oral administration. RESULTS: CENPs showed acceptable particle size and percent entrapment efficiency. In vitro cytotoxicity studies in terms of 50% cell growth inhibition values demonstrated ∼19-fold reduction when treated with CENPs as compared to pure CUR. ∼91-fold increase in Cmax and ∼95-fold increase in AUC0-12h were observed indicating a significant enhancement in the oral bioavailability of CUR when orally administered as CENPs compared to pure CUR. The in vivo anti-cancer study performed with CENPs showed a significant increase in efficacy compared with pure CUR, as observed by tumor volume, body weight and survival rate. CONCLUSIONS: The results clearly indicate that the developed polymeric nanoparticles offer a great potential to improve bioavailability and anticancer efficacy of hydrophobic chemotherapeutic drug.

Highly water-soluble mast cell stabiliser-encapsulated solid lipid nanoparticles with enhanced oral bioavailability.

Cromolyn sodium (CS), a mast cell stabiliser, is widely employed for the prevention and treatment of allergic conditions. However, high hydrophilicity and poor oral permeability hinder its oral clinical translation. Here, solid lipid nanoparticles (SLNs) have been developed for the purpose of oral bioavailability enhancement. The CS-SLNs were engineered by double emulsification method (W1/O/W2) and optimised by using Box-Behnken experimental design. The surface and solid-state characterisations revealed the presence of CS in an amorphous form without any interactions inside the spherical-shaped SLNs. The in-vitro release study showed an extended release up to 24 hr by diffusion controlled process. Ex-vivo and in-vivo intestinal permeation study showed ∼2.96-fold increase in permeability of CS by presentation as SLNs (p < 0.05). Further, in-vivo pharmacokinetic study exhibited ∼2.86-fold enhancements in oral bioavailability of CS by encapsulating inside SLNs, which clearly indicate that SLNs can serve as the potential therapeutic carrier system for oral delivery of CS.

ß-Caryophyllene-Loaded Microemulsion-Based Topical Hydrogel: A Promising Carrier to Enhance the Analgesic and Anti-Inflammatory Outcomes.

Musculoskeletal pain and inflammation can vary from localised pain like pain in the shoulders and neck to widespread pain like fibromyalgia, and as per estimates, around 90% of humans have experienced such pain. Oral non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for such conditions but are associated with concerns like gastric irritation and bleeding. In the present study, a microemulsion-based gel comprising ß-caryophyllene, isopropyl myristate, Tween 80, and normal saline was prepared as a topical option for managing topical pain and inflammation. The globules of the microemulsion were below 100 nm with a zetapotential of around -10 mV. The drug entrapment was >87% with a drug loading of >23%. The permeation studies established better skin permeation (20.11 ± 0.96 µg cm-2 h-1) and retention of the drug (4.96 ± 0.02%) from the developed system vis-à-vis the conventional product (9.73 ± 0.35 µg cm-2 h-1; 1.03 ± 0.01%). The dermatokinetic studies established the better pharmacokinetic profile of the bioactive in the epidermis and dermis layers of the skin. The anti-inflammatory potential in carrageenan-induced rat paw oedema was more pronounced than the conventional product (~91% vis-à-vis ~77%), indicating a better pharmacodynamic outcome from the developed system. The nanotechnology-based natural bioactive product with improved efficacy and drug loading can provide a better alternative for the management of musculoskeletal pain.

2 Receptor Specific Ligand Conjugated Nanocarriers: An Effective Strategy for Targeted Therapy of Tuberculosis.

Tuberculosis (TB) is an ancient chronic disease caused by the bacillus Mycobacterium tuberculosis, which has affected mankind for more than 4,000 years. Compliance with the standard conventional treatment can assure recovery from tuberculosis, but the emergence of drug-resistant strains poses a great challenge for the effective management of tuberculosis. The process of discovery and development of new therapeutic entities with better specificity and efficacy is unpredictable and time-consuming. Hence, delivery of pre-existing drugs with improved targetability is the need of the hour. Enhanced delivery and targetability can ascertain improved bioavailability, reduced toxicity, decreased frequency of dosing and therefore better patient compliance. Nanoformulations are being explored for effective delivery of therapeutic agents, however, optimum specificity is not guaranteed. In order to achieve specificity, ligands specific to receptors or cellular components of macrophage and Mycobacteria can be conjugated to nanocarriers. This approach can improve localization of existing drug molecules at the intramacrophageal site where the parasites reside, improve targeting to the unique cell wall structure of Mycobacterium or improve adhesion to the epithelial surface of intestine or alveolar tissue (lectins). The present review focuses on the investigation of various ligands like Mannose, Mycolic acid, Lectin, Aptamers, etc., installed nanocarriers that are being envisaged for targeting antitubercular drugs.

Role of natural products in alleviation of rheumatoid arthritis-A review.

Rheumatoid arthritis (RHA) is one of the most prevalent complex, chronic, inflammatory diseases, manifested by elevated oxidative stress and inflammatory biomarkers. Prolonged administration of NSAIDs, steroids, and DMARDs, used in the treatment of RHA, is associated with deleterious side effects. This necessitates the urge of new and safe approaches for RHA management, based on the complementary and alternative system of medicine. Documented evidences have suggested that supplementation with nutritional, dietary, and herbal components; can play a crucial role as an adjuvant, in the alleviation of the RHA symptoms, through their influence on the pathological inflammatory processes. Dietary phenolic compounds, flavonoids, carotenoids, and alkaloids with their ability to modulate prooxidant and pro-inflammatory pathways, have been effective in delaying the arthritic disease progression. Moreover, in scientific explorations, herbs containing phenolic compounds, alkaloids, carotenoids flavonoids, spices such as ginger, turmeric, Ayurvedic formulations, different diets such as Mediterranean diet, vegan diet, beverages, and oils such as sesame oil, rice bran oil, vitamins, and probiotics are proven to modulate the action of inflammatory molecules, involved in RHA pathology. Subsequently, the purpose of this review article is to summarize various in vitro, in vivo, and clinical studies in RHA, which have documented remarkable insights into the anti-inflammatory, antioxidant, analgesic, and immunomodulatory, bone erosion preventing properties of dietary, nutritional, and herbal components with the focus on their molecular level mechanisms involved in RHA. Even though major findings were derived from in vitro studies, several in vivo and clinical studies have established the use of diet, herbal, and nutritional management in RHA treatment. PRACTICAL APPLICATIONS: Thickening of the synovial membrane, bone erosion, and cartilage destruction is known to trigger rheumatoid arthritis causing inflammation and pain in bone joints. Continuous intake of NSAIDs, steroids, and DMARD therapy are associated with detrimental side effects. These side effects can be overcome by the use of dietary, nutritional, and herbal interventions based on the complementary and alternative therapy. This concept portrays the food components and other natural components having the potential to promote health, improve general well-being, and reduce the risk of RHA.

Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis.

Tuberculosis (TB) is a potentially fatal contagious disease and is a second leading infectious cause of death in the world. Osteoarticular TB is treated using standard regimen of 1st and 2nd line anti-tubercular drugs (ATDs) for extensive period of 8-20 months. These drugs are commonly administered in high doses by oral route or by intravenous route, because of their compromised bioavailability. The common drawbacks associated with conventional therapy are poor patient compliance due to long treatment period, frequent and high dosing, and toxicity. This aspect marks for the need of formulations to eliminate these drawbacks. MTB is an intracellular pathogen of mononuclear phagocyte. This attribute makes nanotherapeutics an ideal approach for MTB treatment as macrophages capture nano forms. Polymeric nanoparticles are removed from the body by opsonization and phagocytosis, which forms an ideal strategy to target macrophage containing mycobacteria. To further improve targetability, the nanoparticles are conjugated with ligand, which serves as an easy substrate for the receptors present on the macrophage surface. The purpose of present work was to develop intra-articular injectable in situ gelling system containing polymeric nanoparticles, which would have promising advantages over conventional method of treatment. The rationale behind formulating nanoparticle incorporated in situ gel-based system was to ensure localization of the formulation in intra-articular cavity along with sustained release and conjugation of nanoparticles with mannose as ligand to improve uptake by macrophages. Rifampicin standard ATD was formulated into chitosan nanoparticles. Chitosan with 85% degree of deacetylation (DDA) and sodium tripolyphosphate (TPP) as the crosslinking agent was used for preparing nanoparticles. The percent entrapment was found to be about 71%. The prepared nanoparticles were conjugated with mannose. Conjugation of ligand was ascertained by performing Fourier transformed infrared spectroscopy. The particle size was found to be in the range of 130-140 nm and zeta potential of 38.5 mV. Additionally, we performed scanning electron microscopy to characterize the surface morphology of ligand-conjugated nanoparticles. The conjugated chitosan nanoparticles were incorporated into in situ gelling system comprising Poloxamer 407 and HPMC K4M. The gelling system was evaluated for viscosity, gelling characteristics, and syringeability. The drug release from conjugated nanoparticles incorporated in in situ gel was found to be about 70.3% at the end of 40 h in simulated synovial fluid following zero-order release kinetics. Based on the initial encouraging results obtained, the nanoparticles are being envisaged for ex vivo cellular uptake study using TB-infected macrophages.

Emerging advances in cationic liposomal cancer nanovaccines: opportunities and challenges.

Advancements in the field of cancer therapeutics have witnessed a recent surge in the use of liposomes. The physicochemical characteristics of the liposomes and their components, including the lipid phase transition temperature, vesicular size and size distribution, surface properties, and route of administration, play a significant role in the modulation of the immune response as an adjuvant and for loaded antigen (Ag). Cationic liposomes, concerning their potential ability to amplify the immunogenicity of the loaded Ag/adjuvant, have received enormous interest as a promising vaccine delivery platform for cancer immunotherapy. In the present review, the physicochemical considerations for the development of Ag/adjuvant-loaded liposomes and the cationic liposomes' effectiveness for promoting cancer immunotherapy have been summarized.

A Critical Review on Anticancer Mechanisms of Natural Flavonoid Puerarin.

Cancer is one of the prominent global causes of death and the foremost worldwide health concern. Despite unprecedented progress in cancer chemoprevention, a vast number of cancers, however, remain an undefeatable challenge for treatment modalities. Immense therapeutic activities of puerarin contribute to its use in various health disorders. In this review, we explored the potential molecular mechanisms and targets of puerarin, proving its potential as a novel anticancer agent, for future cancer therapy and chemoprevention. Several mechanisms account for anticancer activity of puerarin which includes downregulation of NF-kB signalling pathway, mTOR signalling pathway, PI3K and BCl-2 proteins and upregulation of miR-16, caspase proteins, c- Jun N terminal kinase and extracellular signal-regulated kinase 1/2. These alterations result in inhibition of cancer cell proliferation and/or induction of apoptosis. Understanding the molecular mechanisms involved in chemotherapy and chemoprevention could aid in the more pronounced exploration of puerarin in effective cancer treatment.

Significance of Ligand-Anchored Polymers for Drug Targeting in the Treatment of Colonic Disorders.

Treatment of a variety of bowel diseases like Crohn's disease, ulcerative colitis, colonic cancers, colonic pathologies, and systemic delivery of drugs at the target sites can be done with the help of targeted drug delivery technique. Conventional colon specific drug delivery systems lack specificity and release significant amount of drug prior reaching the target site. Hence, efficient drug delivery system that ensures effective release of the drug at the colon is still a sought after research arena. Ligand anchored therapy is a strong and effective approach to execute drug delivery in selective target cells, for both, diagnostic, as well as therapeutic reasons. Compared to the regular drugs, such ligand anchored therapy provides added benefit of minimum toxicity and few side effects. Discovery of overexpressed receptors on diseased cells, as compared to healthy cells led to the emergence of active drug targeting. Further, drug resistance constitutes one of the major reasons of the failure of chemotherapy and presents a major obstacle for the effective treatment. The reason behind drug resistance is exposure of pathological cells/pathogens to sub-therapeutic levels of drugs due lack of specificity of therapeutics. Active targeting, specifically taken up by the target cells, can warrant exposure of pathological cells/pathogens to high drug load at the target and sparing non-target cells hence minimal damage to normal cells and least chance of drug resistance. Many ligands like antibodies, aptamers, peptides, folate, and transferrin have been discovered in the past few years. The design of nanocarriers can be incorporated with many different functions which enables functions like imaging and triggered intracellular drug release. The present review article focuses on advances in ligand anchored therapy and its significance on the progress of targeted nanocarriers. It will also establish novel concepts like multi-targeting and multi-functional nanocarriers for the treatment of colonic disorders.

Bone Health and Natural Products- An Insight.

Bone metabolism involves a complex balance between matrix deposition, mineralization, and resorption. Numerous evidences have revealed that dietary components and phytoconstituents can influence these processes, through inhibition of bone resorption, thus exhibiting beneficial effects on the skeleton. Various traditional herbal formulae in ayurvedic and Chinese medicine have shown demonstrable benefits in pharmacological models of osteoporosis. The present review discusses normal bone metabolism and disorders caused by bone disruption, with particular reference to osteoporosis and current therapeutic treatment. Furthermore the effects of constituents from natural products on bone tissue are explained, with relevant evidences of efficacy in various experimental models.

Mannose-conjugated curcumin-chitosan nanoparticles: Efficacy and toxicity assessments against Leishmania donovani.

Aim was to fabricate and optimize CUR-loaded mannose-functionalized chitosan nanoparticles (Cur-MCN) which overcome the limitations of drugs to reach the intracellular locations and to establish its therapeutic potential in visceral leishmaniasis by targeting of CUR to macrophages. Cur-MCN were developed by mannose-conjugated chitosan and have been tested for their efficacy and toxicit. In vivo antileishmanial activity in hamsters has shown significantly greater suppression of parasite replication in the spleen with Cur-MCN than unconjugated chitosan nanoparticles. The in vitro cytotoxicity study against the J774A.1 cell line demonstrated its comparative non-toxicity towards the macrophage cells. The potential of Cur-MCN was also confirmed by minimal observed cytotoxicity in our in vivo studies.

Phytochemicals and PI3K Inhibitors in Cancer-An Insight.

In today's world of modern medicine and novel therapies, cancer still remains to be one of the prime contributor to the death of people worldwide. The modern therapies improve condition of cancer patients and are effective in early stages of cancer but the advanced metastasized stage of cancer remains untreatable. Also most of the cancer therapies are expensive and are associated with adverse side effects. Thus, considering the current status of cancer treatment there is scope to search for efficient therapies which are cost-effective and are associated with lesser and milder side effects. Phytochemicals have been utilized for many decades to prevent and cure various ailments and current evidences indicate use of phytochemicals as an effective treatment for cancer. Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling cascades is a common phenomenon in most types of cancers. Thus, natural substances targeting PI3K pathway can be of great therapeutic potential in the treatment of cancer patients. This chapter summarizes the updated research on plant-derived substances targeting PI3K pathway and the current status of their preclinical studies and clinical trials.

Cromolyn sodium encapsulated PLGA nanoparticles: An attempt to improve intestinal permeation.

High hydrophilicity curtails the intestinal permeation of cromolyn sodium (CS) which in turn compels to compromise with its multiple biological activities. Hence, the present research was intended with an objective to develop CS encapsulated polylactide-co-glycolide (PLGA) nanoparticles (CS-PNs) for enhancing intestinal permeation. The CS-PNs were prepared by double emulsification solvent evaporation method (W1/O/W2). The "Quality by Design" approach using box-behnken experimental design was employed to enhance encapsulation of CS inside CS-PNs without compromising with particle size. The polymer concentration, surfactant concentration and organic/aqueous phase ratio significantly affected the physicochemical properties of CS-PNs. The optimized CS-PNs were subjected to various solid-state and surface characterization studies using FTIR, DSC, XRD, TEM and AFM, which pointed towards the encapsulation of CS inside the spherical shaped nanoparticles without any physical as well as chemical interactions. Ex-vivo intestinal permeation study demonstrated ∼4 fold improvements in CS permeation by forming CS-PNs as compared to pure CS. Further, in-vivo intestinal uptake study performed using confocal microscopy, after oral administration confirmed the permeation potential of CS-PNs. Thus, the findings of the studies suggest that CS-PNs could provide a superior therapeutic carrier system of CS, with enhanced intestinal permeation.

Lipopolysaccharide based oral nanocarriers for the improvement of bioavailability and anticancer efficacy of curcumin.

Soluthin MD(®), a unique phosphatidylcholine-maltodextrin based hydrophilic lipopolysaccharide, which exhibits superior biocompatibility and bioavailability enhancer properties for poorly water soluble drug(s). Curcumin (CUR) is a potential natural anticancer drug with low bioavailability due to poor aqueous solubility. The study aims at formulation and optimization of CUR loaded lipopolysaccharide nanocarriers (C-LPNCs) to enhance oral bioavailability and anticancer efficacy in colon-26 tumor-bearing mice in vitro and in vivo. The Optimized C-LPNCs demonstrated favorable mean particle size (108 ± 3.4 nm) and percent entrapment efficiency (65.29 ± 1.0%). Pharmacokinetic parameters revealed ∼130-fold increase in oral bioavailability and cytotoxicity studies demonstrated ∼23-fold reduction in 50% cell growth inhibition when treated with optimized C-LPNCs as compared to pure CUR. In vivo anticancer study performed with optimized C-LPNCs showed significant increase in efficacy compared with pure CUR. Thus, lipopolysaccharide nanocarriers show potential delivery strategy to improve oral bioavailability and anticancer efficacy of CUR in the treatment of colorectal cancer.

Mannose-conjugated chitosan nanoparticles loaded with rifampicin for the treatment of visceral leishmaniasis.

The aim of current research work was to develop and investigate the potential of rifampicin (RIF) loaded mannose-conjugated chitosan nanoparticulate system for selective delivery to the macrophages in the management of visceral leishmaniasis (VL). RIF loaded mannose-conjugated chitosan nanoparticles (mCNPs) were prepared and characterized for shape, size, entrapment efficiency and in vitro drug release. The in vivo bio-distribution in albino rats and ex vivo drug uptake by macrophage were also evaluated. It was observed that extent of accumulation of mCNPs in macrophage rich organs, particularly in liver and spleen, were significantly higher compared to free drug. Ex vivo uptake of mCNPs was 2.31 times higher compared to unconjugated chitosan nanoparticles (CNPs). The macrophage uptake of mCNPs was inhibited significantly on pre-incubation with 0.05 M mannose in a parallel experiment, being suggestive of receptor mediated uptake of mannosylated nanoparticles. Our results indicate that mCNPs could be a promising carrier for selective delivery of RIF to macrophages for effective management of VL.

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis.

OBJECTIVE: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL). METHODS: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy. RESULTS: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system. CONCLUSIONS: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.