Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin.

This study tests the hypothesis that association complexes formed between enoxaparin and cetyltrimethylammonium bromide (CTAB) augment permeation across the gastrointestinal mucosa due to improved encapsulation of this hydrophilic macromolecule within biocompatible poly (lactide-co-glycolide, PLGA RG 503) nanoparticles. When compared with free enoxaparin, association with CTAB increased drug encapsulation efficiency within PLGA nanoparticles from 40.3 ± 3.4 to 99.1 ± 1.0%. Drug release from enoxaparin/CTAB PLGA nanoparticles was assessed in HBSS, pH 7.4 and FASSIFV2, pH 6.5, suggesting effective protection of PLGA-encapsulated enoxaparin from unfavorable intestinal conditions. The stability of the enoxaparin/CTAB ion pair complex was pH-dependent, resulting in more rapid dissociation under simulated plasma conditions (i.e., pH 7.4) than in the presence of a mild acidic gastrointestinal environment (i.e., pH 6.5). The intestinal flux of enoxaparin complexes across in vitro Caco-2 cell monolayers was greater when encapsulated within PLGA nanoparticles. Limited changes in transepithelial transport of PLGA-encapsulated enoxaparin complexes in the presence of increasing CTAB concentrations suggest a significant contribution of size-dependent passive diffusion as the predominant transport mechanism facilitating intestinal absorption. Graphical abstract.

Improved Oral Bioavailability, Therapeutic Efficacy, and Reduced Toxicity of Tamoxifen-Loaded Liquid Crystalline Nanoparticles.

Present investigation deals with formulation and evaluation of tamoxifen (TMX)-loaded liquid crystalline nanoparticles (TMX-LCNPs) for improving oral bioavailability and safety of the existing treatment. Hexagonal Glyceryl monooleate-based TMX-LCNPs (GLCNPs) and Phytantriol-based TMX-LCNPs (PLCNPs) were prepared by dilution-through-hydrotrope method for oral administration. Oleic acid was incorporated in the lipid matrix to enhance the drug loading in the LCNPs. Optimized LCNPs displayed small particle size with a narrow distribution, sustained drug release and high gastrointestinal stability. TMX-LCNPs were found to be considerably higher cytotoxic to MCF-7 cells as compared to free TMX. Substantial fold enhancement in oral bioavailability (~7- and ~5-folds with TMX-GLCNPs and TMX-PLCNPs, respectively) was evident followed by significant reduction in tumor burden with lesser hepatotoxicity. Out of the two LCNP formulations, PLCNPs were found to be better in convalescing the disease.

Phytantriol Based "Stealth" Lyotropic Liquid Crystalline Nanoparticles for Improved Antitumor Efficacy and Reduced Toxicity of Docetaxel.

PURPOSE: The present work focuses on design and development of surface functionalized LCNPs for improving tumor delivery of DTX. METHODS: Phytantriol based "stealth" LCNPs were prepared using hydrotrope method and optimized. The potential of developed formulation was further assessed using cell culture experiments, in vivo pharmacokinetics, in vivo pharmacodynamics and toxicity studies. RESULTS: A biphasic drug release pattern was observed with sustained release of drug till 72 h. In vitro cell culture experiments revealed efficient internalization within MCF-7 cells with 25.80-fold decrease in IC50 value for PEG-LCNPs as compared to free DTX. Mechanistic insights demonstrated preferential co-localization of LCNPs in the vicinity of the nucleus. Furthermore, in vivo pharmacokinetic studies revealed 14.45-fold enhancement in circulation half-life of PEG-LCNPs as compared to marketed formulation Taxotere®. In vivo efficacy studies PEG-LCNPs in DMBA induced breast cancer model revealed ~81% reduction in the tumor burden compared to Taxotere® which caused/achieve only 47% reduction or showed only 47% decrease. Furthermore, safety profile was noted for PEG-LCNPs as compared to Taxotere®, measured as a function of hepato- and nephro-toxicity. CONCLUSIONS: Surface functionalization of LCNPsis a viable approach for improving the therapeutic potential of DTX.

Lyotropic liquid crystalline nanoparticles of CoQ10: implication of lipase digestibility on oral bioavailability, in vivo antioxidant activity, and in vitro-in vivo relationships.

The present investigation reports implications of the lipase digestibility of lyotropic liquid crystalline nanoparticles (LCNPs) on the oral bioavailability, in vivo antioxidant potential, and in vitro-in vivo relationship (IVIVR) of CoQ10 loaded LCNPs prepared from glyceryl monooleate (GLCQ) and phytantriol (PLCQ). Exhaustive optimization of the process variables was carried out, and optimized lyophilized formulations were found to have particle sizes of 140.45 ± 5.47 nm and 238.42 ± 8.35 nm and a polydispersity index (PDI) of 0.15 ± 0.01 and 0.22 ± 0.03 for GLCQ and PLCQ, respectively. The entrapment efficiency at 10% theoretical loading was found to be >90% in both the cases. The morphological characteristics of the developed formulations were assessed using high resolution transmission electron microscopy and small-angle X-ray scattering analysis, which showed hexagonal (HII) structure. The developed formulations were also found to be stable in simulated gastrointestinal fluids for the stipulated period of time. The in vitro drug release studies revealed a bimodal sustained release drug profile with Higuchi type release kinetics as the best fit release model for both the formulations. The best fit release models were found to be of the Hixson Crowell type in the case of GLCQ when carried out in lipase rich media, suggestive of matrix erosion and subsequent formation of secondary structures, which was further corroborated by carrier degradation studies. Furthermore, 9.1- and 10.67-fold increase in Caco-2 cell uptake was observed in the case of GLCQ and PLCQ, respectively, attributed to the formation of the virtual channel pathway as a probable absorption mechanism. Consequently, 7.09- and 8.67-fold increase in oral bioavailability was observed in the case of GLCQ and PLCQ, respectively. The IVIVR was also established with r(2) values in the order of 0.996 and 0.999 for GLCQ and PLCQ, respectively, in contrast to that of 0.484 for free CoQ10. Finally, in vivo prophylactic antioxidant efficacy against the STZ-treated rats using various markers such as GSH, LDH, SOD, MDA, glucose level, and body weight showed significantly higher antioxidant activity of CoQ10-LCNPs as compared to that of free CoQ10. In a nutshell, the developed formulation strategy poses great potential in improving the oral bioavailability of difficult-to-deliver drugs such as CoQ10.

Bicontinuous cubic liquid crystalline nanoparticles for oral delivery of Doxorubicin: implications on bioavailability, therapeutic efficacy, and cardiotoxicity.

PURPOSE: The present study explores the potential of bicontinous cubic liquid crystalline nanoparticles (LCNPs) for improving therapeutic potential of doxorubicin. METHODS: Phytantriol based Dox-LCNPs were prepared using hydrotrope method, optimized for various formulation components, process variables and lyophilized. Structural elucidation of the reconstituted formulation was performed using HR-TEM and SAXS analysis. The developed formulation was subjected to exhaustive cell culture experiments for delivery potential (Caco-2 cells) and efficacy (MCF-7 cells). Finally, in vivo pharmacokinetics, pharmacodynamic studies in DMBA induced breast cancer model and cardiotoxicity were also evaluated. RESULTS: The reconstituted formulation exhibited Pn3m type cubic structure, evident by SAXS and posed stability in simulated gastrointestinal fluids and at accelerated stability conditions for 6 months. Dox-LCNPs revealed significantly higher cell cytotoxicity (16.23-fold) against MCF-7 cell lines as compared to free drug owing to its preferential localization in the vicinity of nucleus. Furthermore, Caco-2 cell experiments revealed formation of reversible "virtual pathways" in the cell membrane for Dox-LCNPs and hence posed significantly higher relative oral bioavailability (17.74-fold). Subsequently, Single dose of Dox-LCNPs (per oral) led to significant reduction in % tumor burden (~42%) as compared that of ~31% observed in case of Adriamycin® (i.v.) when evaluated in DMBA induced breast cancer model. Moreover, Dox induced cardiotoxicity was also found to be significantly lower in case of Dox-LCNPs as compared to clinical formulations (Adriamycin® and Lipodox®). CONCLUSION: Incorporation of Dox in the novel LCNPs demonstrated improved antitumor efficacy and safety profile and can be a viable option for oral chemotherapy.

Enhanced antitumor efficacy and counterfeited cardiotoxicity of combinatorial oral therapy using Doxorubicin- and Coenzyme Q10-liquid crystalline nanoparticles in comparison with intravenous Adriamycin.

Present study focuses on enhancing oral antitumor efficacy and safety of Dox-LCNPs in combination with CoQ10-LCNPs. Drug-loaded-LCNPs were prepared by solvent-diffusion-evaporation method and optimized. Median effect analysis suggested dose-reduction-index of 16.84- and 5.047-fold and strong synergism for combination at 1:10 dose ratio owing to higher cellular uptake, nuclear colocalization, higher apoptotic index and 8-OHdG levels. The prophylactic antitumor efficacy of the CoQ10-LCNPs was also established using tumor induction and progression studies. Finally, therapeutic antitumor efficacy was found to be significantly higher (~1.76- and ~4.5-fold) for the combination as compared to Dox-LCNPs (per oral) and Adriamycin (i.v.) respectively. Notably, level of residual tumor burden was insignificant (P>0.05) after 30days in case of combination and LipoDox® (i.v.). Interestingly, with Dox-induced-cardiotoxicity was completely counterfeited in combination. In nutshell, LCNPs pose great potential in improving the therapeutic efficacy of drugs by oral route of administration. FROM THE CLINICAL EDITOR: This study describes the use of liquid crystalline nanoparticles containing coenzyme Q10 and doxorubicin. The nano-conjugates not only provided an enhanced oral treatment option for a tumor model, but prevented cardiotoxicity, a major complication of this drug when delivered via conventional methods.

Gelatin coated hybrid lipid nanoparticles for oral delivery of amphotericin B.

Amphotericin B (AmB) loaded polymer lipid hybrid nanoparticles (AmB-PLNs) comprised of lecithin (anionic lipid) and gelatin (Type A, cationic below its isoelectric point 7.0-9.0) were prepared by a two-step desolvation method to improve the oral bioavailability of AmB. The optimized AmB-PLNs were found to have particle size 253 ± 8 nm, polydispersity index (PDI) 0.274 ± 0.008, and entrapment efficiency 50.61 ± 2.20% at 6% w/w of initial theoretical drug loading. Scanning electron microscopy (SEM) revealed spherical shaped nanoparticles whereas confocal laser scanning electron microscopy (CLSM) and fluorescent resonance energy transfer (FRET) analysis confirmed the orientation of the lecithin (located in the core) and gelatin (exterior coat) within the system. The developed formulation exhibited a sustained drug release profile with a release pattern best fitted to Higuchi kinetics. Experiments on Caco-2 cell lines revealed a 5.89-fold increase in the intestinal permeability of AmB-PLNs whereas in vivo pharmacokinetic studies exhibited a 4.69-fold increase in the oral bioavailability upon incorporation of AmB into PLNs as compared to that of free drug. The developed formulation showed significantly lesser hemolytic toxicity as compared to the free drug, Fungizone (micellar solution of AmB) and Fungisome (liposomal formulation of AmB). Furthermore, blood urea nitrogen (BUN) and plasma creatinine levels, indicative of nephrotoxicity, were also found to be significantly lesser for developed PLN formulation as compared to free drug and Fungizone while comparable to that of Fungisome. The histopathology of the kidney tissues further confirmed the absence of any changes in the morphology of the renal tubules.

Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes).

The present study explores the potential of polyelectrolyte-coated liposomes for improving the oral deliverability of doxorubicin (Dox). As a part of formulation strategy, stearyl amine was selected as a formulation component to provide positive charge to liposomes, which were subsequently coated with anionic poly(acrylic acid) (PAA) followed by coating of cationic polyallyl amine hydrochloride (PAH) in a layer by layer manner and led to the formation of a robust structure "layersomes". Optimization of various process variables were carried out, and optimized formulation was found to have particle size of 520.4 ± 15.0 nm, PDI of 0.312 ± 0.062, ζ potential of +30.4 ± 5.32 mV, and encapsulation efficiency of 63.4 ± 4.26%. Layersomes were not only stable in simulated gastrointestinal fluids but also presented sustained drug release (∼35%) as compared to both Dox-liposomes and PAA-Dox-liposomes (∼67%), the release pattern being Higuchi kinetics. The in vivo pharmacokinetics studies revealed about 5.94-fold increase in oral bioavailability of Dox as compared to free drug. In vivo antitumor efficacy in a DMBA-induced breast tumor model further exhibited significant reduction in the tumor growth as compared to control and IV-Dox, while results were comparable to IV-LipoDox. Layersomes also exhibited a marked reduction in cardiotoxicity in comparison with IV-doxorubicin and IV-LipoDox (marketed formulation), as evidenced by the reduced levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and increased levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of layersomes was further confirmed by comparative histopathological examination of heart tissue after treatment with various formulations. The positive results of the study strengthen our expectation that the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of poorly bioavailable drugs and can open new vistas for oral chemotherapy.

Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug.

Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (Seq) in the SNEDDS (superSNEDDS, 250% of Seq). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of Seq), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% Seq in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48 h to 1 month under ambient conditions. The PK study in rats displayed significantly higher Cmax and AUC0-7h (3-fold increase) and faster Tmax for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.

Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model.

The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 ± 2.30% and 160.20 ± 0.99 nm, respectively, and freeze-dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC(50) of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs.

Synthesis, Characterization, and Biodistribution of Quantum Dot-Celecoxib Conjugate in Mouse Paw Edema Model.

Increased risk of cardiovascular side effects has been reported with many of the drugs in the market, including nonsteroidal anti-inflammatory drugs (NSAIDs). Hence, it is critical to thoroughly evaluate the biodistribution and pharmacokinetic properties of the drugs. Presently nanotechnology in combination with noninvasive imaging techniques such as magnetic resonance imaging (MRI), computed axial tomography (CAT), and positron emission tomography (PET) provides a better estimate of the spatio-temporal distribution of therapeutic molecules. Optical imaging using quantum dot- (QD-) tagged biological macromolecules is emerging as a fast, economical, sensitive, and safer alternative for theranostic purposes. In the present study, we report the nanoconjugates of mercaptopropionic acid- (MPA-) capped CdTe quantum dots (QDs) and Celecoxib for bio-imaging in carrageenan-induced mouse paw edema model of inflammation. QD-Celecoxib conjugates were characterized by fluorescence, FT-IR, NMR, and zeta-potential studies. In vivo imaging of QD-Celecoxib conjugates showed clear localization in the inflamed tissue of mouse paw within 3 h, with a gradual increase reaching a maximum and a later decline. This decrease of fluorescence in the paw region is followed by an increase in urinary bladder region, suggesting the possible excretion of QD-drug conjugates from mice within 24 h.

High payload nanostructured lipid carriers fabricated with alendronate/polyethyleneimine ion complexes.

Oral bioavailability of the anti-osteoporotic drug alendronate (AL) is limited to ≤ 1% due to unfavorable physicochemical properties. To augment absorption across the gastrointestinal mucosa, an ion pair complex between AL and polyethyleneimine (PEI) was formed and incorporated into nanostructured lipid carriers (NLCs) using a modified solvent injection method. When compared to free AL, ion pairing with PEI increased drug encapsulation efficiency in NLCs from 10% to 87%. Drug release from NLCs measured in vitro using fasted state simulated intestinal fluid, pH 6.5 (FaSSIF-V2) was significantly delayed after PEI complexation. Stability of AL/PEI was pH-dependent resulting in 10-fold faster dissociation of AL in FaSSIF-V2 than measured at pH 7.4. Intestinal permeation properties estimated in vitro across Caco-2 cell monolayers revealed a 3-fold greater flux of AL encapsulated as hydrophobic ion complex in NLCs when compared to AL solution (Papp = 8.43 ± 0.14 × 10-6 cm/s and vs. 2.76 ± 0.42 × 10-6 cm/s). Cellular safety of AL/PEI-containing NLCs was demonstrated up to an equivalent AL concentration of 2.5 mM. These results suggest that encapsulation of AL/PEI in NLCs appears a viable drug delivery strategy for augmenting oral bioavailability of this clinically relevant bisphosphonate drug and, simultaneously, increase gastrointestinal safety.

Role of Antioxidants for the Treatment of Cardiovascular Diseases: Challenges and Opportunities.

Cardiovascular disorders or cardiovascular diseases (CVD) are major illness associated with heart and blood vessels. Reactive oxygen species (ROS), generated during excessive oxidative stress, are responsible for the pathophysiology of various cardiovascular disorders including atherosclerosis, cardiac hypertrophy, cardiomyopathy, heart failure, ventricular remodeling, ischemia/reperfusion injury and myocardial infarction. Cellular "redox homeostasis" generally maintains the healthy physiology in cardiac myocytes and endothelial cells. However, during excessive oxidative stress body's endogenous system fails to maintain normal physiology hence antioxidant supplementation is necessary, which could scavenge the free radicals and other toxic radicals. Several antioxidants such as CoQ10, beta carotene, lycopene, quercetin, reserveterol, vitamin C and vitamin E have shown preventive and therapeutic benefits in different forms of CVD. However, poor biopharmaceutical properties and variable pharmacokinetics of several antioxidants limits their use as therapeutic agents. Hence delivery of stable antioxidants at their site of action is a need of current scenario. Several novel carriers based approaches have shown considerable benefits for the systemic and site specific delivery of antioxidants for the preventive and therapeutic treatment of several cardiovascular diseases. In the present review, conventional as well as novel antioxidants have been discussed with special emphasis for the treatment of CVD. Further, the current review also highlights the critical challenges for antioxidant delivery and various novel carriers (nanoformulations) including, liposomes and nanoparticles explored for their efficient delivery in the therapeutic management of CVD.

Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel.

Paclitaxel (PTX) loaded layersome formulations were prepared using layer-by-layer assembly of the polyelectrolytes over liposomes. Stearyl amine was utilized to provide positive charge to the liposomes, which were subsequently coated with anionic polymer polyacrylic acid (PAA) followed by coating of cationic polymer polyallylamine hydrochloride (PAH). Optimization of various process variables were carried out and optimized formulation was found to have particle size of 226 ± 17.61 nm, PDI of 0.343 ± 0.070, zeta potential of +39.9 ± 3.79 mV and encapsulation efficiency of 71.91 ± 3.16%. The developed formulation was further subjected to lyophilization using a universal stepwise freeze drying cycle. The lyophilized formulation was found to be stable in simulated gastrointestinal fluids and at accelerated stability conditions. In vitro drug release studies revealed that layersome formulation was able to sustain the drug release for 24 h; release pattern being Higuchi kinetics. Furthermore, cell culture experiments showed higher uptake of layersomes from lung adenocarcinoma (A549) cell lines as compared to free drug. This was subsequently corroborated by MTT assay, which revealed IC50 value of 29.37 µg/ml for developed layersome formulation in contrast to 35.42 µg/ml for free drug. The in vivo pharmacokinetics studies revealed about 4.07 fold increase in the overall oral bioavailability of PTX as compared to that of free drug. In vivo antitumor efficacy in DMBA induced breast tumor model showed significant reduction in the tumor growth as compared to the control and comparable to that of i.v. Taxol(®). In addition, the toxicity studies were carried out to confirm the safety profile of the developed formulation and it was found to be significantly higher as compared to Taxol(®). Therefore, the developed formulation strategy can be fruitfully exploited to improve the oral deliverability of difficult-to deliver drugs.

Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy.

A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2 ± 2.5% in 24 h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3 ± 10.2 to 4.4 ± 1.3%) and control the release of PTX (43.6 ± 3.2% released in 24 h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24 h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel.

Preparation and characterization of niosomal gel for iontophoresis mediated transdermal delivery of isosorbide dinitrate.

The purpose of the present study was to improve the bioavailability of isosorbide dinitrate (ISDN) through transdermal route by using cationic niosomal gel as a carrier with anodic iontophoresis. ISDN-loaded cationic niosomes prepared by thin film hydration technique had an average diameter of 262 ± 6.92 nm, polydispersity index of 0.217 ± 0.02, zeta potential of +25.4 ± 0.12, and entrapment efficiency of 68.16 ± 1.14%. The prepared niosomes were incorporated in minimum quantity of carbopol gel which exhibited thixotropic behavior suitable for transdermal application. While free drug was found to degrade upon application of current, interestingly, it was a found that niosomes offered protection to ISDN from degradation during the iontophoresis. The in vitro permeation studies with different current densities showed increase in transdermal flux and decrease in lag time by 11.15- and 2.42-fold (0.5 mA/cm(2)), 12.66- and 2.58-fold (1.0 mA/cm(2)), and 14.46- and 3.75-fold (1.5 mA/cm(2)), respectively, as compared to passive diffusion of free drug. The study confirms the synergistic effect of niosomes and iontophoresis in improving the transdermal permeation profile of ISDN. The enhanced permeation by iontophoresis was investigated by scanning electron microscopy and it was observed that "latent shunt" around the hair follicles became activated and their pore size also increased upon increasing the current densities. Finally, in vivo skin permeation studies demonstrated 2.47 times increased in transdermal bioavailability of ISDN using niosomes in comparison to free drug. The study confirmed that both niosomes and iontophoresis enhance transdermal permeation by two different mechanisms and combination of both has synergistic effect that resulted in higher transdermal flux of ISDN.

Enhanced dermal delivery of acyclovir using solid lipid nanoparticles.

The present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir (ACV) and evaluate their potential as the carrier for dermal delivery. ACV-loaded SLNs (ACV-SLNs) were prepared by the optimized double emulsion process using Compritol 888 ATO as solid lipid. The prepared SLNs were smooth and spherical in shape with average diameter, polydispersity index, and entrapment efficiency of 262 ± 13 nm, 0.280 ± 0.01, and 40.08 ± 4.39% at 10% (w/w) theoretical drug loading with respect to Compritol 888 ATO content. Differential scanning calorimetry and powder X-ray diffraction pattern revealed that ACV was present in the amorphous state inside the SLNs. In vitro skin permeation studies on human cadaver and Sprague-Dawley rat skin revealed 17.65 and 15.17 times higher accumulation of ACV-SLNs in the dermal tissues in comparison to commercially available ACV cream after 24 h. Mechanism of topical permeation and dermal distribution was studied qualitatively using confocal laser scanning microscopy. While free dye (calcein) failed to penetrate skin barrier, the same encapsulated in SLNs penetrated deeply into the dermal tissue suggesting that pilosebaceous route was followed by SLNs for skin penetration. Histological examination and transdermal epidermal water loss measurement suggested that no major morphological changes occurred on rat skin surface due to the application of SLNs. Overall, it was concluded that ACV-loaded SLNs might be beneficial in improving dermal delivery of antiviral agent(s) for the treatment of topical herpes simplex infection.

The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen.

The present investigation reports on the conditions for preparation of tamoxifen loaded PLGA nanoparticles (Tmx-NPs) for oral administration. Tmx-NPs with >85% entrapment efficiency and 165.58 ± 3.81 nm particle size were prepared and freeze dried. Freeze dried Tmx-NPs were found to be stable in various simulated GIT media (pH 1.2, pH 3.5, pH 6.8, SGF & SIF). No significant changes in characteristics of Tmx-NPs were observed after 3 months accelerated stability studies. The cell viability in C127I cells was found to be relatively lower in Tmx-NP treated cells as compared to free Tmx treated cells. CLSM imaging reveled that nanoparticles were efficiently localized into the nuclear region of C127I cells. Oral bioavailability of Tmx was increased by 3.84 and 11.19 times as compared to the free Tmx citrate and Tmx base respectively, when formulated in NPs. In vivo oral antitumor efficacy of Tmx-NPs was carried out in DMBA induced breast tumor model and tumor size was reduced up to 41.56% as compared to untreated groups which showed an increase in tumor size up to 158.66%. Finally, Tmx-NPs showed the marked reduction in hepatotoxicty when compared with free Tmx citrate as evidenced by histopathological examination of liver tissue as well as AST, ALT and MDA levels. Therefore Tmx-NPs could have the significant value for the oral chronic breast cancer therapy with reduced hepatotoxicity.

Synthesis, pharmacoscintigraphic evaluation and antitumor efficacy of methotrexate-loaded, folate-conjugated, stealth albumin nanoparticles.

UNLABELLED: The present study aims to develop a multifunctional nanoformulation based on technetium-99m labeled, folate conjugated, methotrexate-loaded human serum albumin nanoparticles (HSA NPs) and explore their potential in cancer theragnostics. MATERIALS & METHODS: Methotrexate-loaded HSA NPs were synthesized by a reverse microemulsion technique, followed by chemical crosslinking with glutaraldehyde. These NPs were conjugated with folic acid (FA) through a hydrophilic polyethylene glycol spacer to render them long-circulatory and augment their tumor-specific localization. The therapeutic conjugate was further radiolabeled with a γ-emitter technetium-99m for real-time monitoring of its blood clearance kinetics and biodistribution through the measurement of blood/organ-associated radioactivity and scintigraphic imaging. RESULTS & CONCLUSION: In vitro cell-uptake and cytotoxicity studies corroborated that FA conjugation enabled these NPs to specifically target and kill folate-receptor overexpressing cancer cells via S phase arrest. Blood clearance kinetics and biodistribution studies clearly indicated that circulation time, as well as tumor-specific localization of methotrexate-loaded HSA nanocarriers, could be significantly augmented upon polyethylene glycolylation and conjugation of FA. Finally, we demonstrated that these targeted HSA NPs inhibited tumor growth more effectively, as compared with the nontargeted controls.

Engineered PLGA nanoparticles: an emerging delivery tool in cancer therapeutics.

Nanocarriers formulated with the US Food and Drug Administration-approved biocompatible and biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) are being widely explored for the controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. Surface functionalization of PLGA nanoparticles has paved the way to a variety of engineered PLGA-based nanocarriers, which, depending on reticular requirements, can demonstrate a wide variety of combined properties and functions such as prolonged residence time in blood circulation, enhanced oral bioavailability, site-specific drug delivery, and tailored release characteristics. The present review highlights the recent leaps in PLGA-based nanotechnology with a particular focus on cancer therapeutics. Starting with a brief introduction to cancer nanotechnology, we then discuss developmental aspects and the in vitro and in vivo efficacy of PLGA-based nanocarriers in terms of targeted drug or gene delivery. The main objective of this review is to convey information about the state of art and to critically address the limitations and the need for further progress and clinical developments in this emerging technology.