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Despite the ongoing extensive research, cancer therapeutics still remains an area with unmet needs which is hampered by shortfall in the development of newer medicines. The present study discusses a nano-based combinational approach for treating solid tumor. Dual-loaded nanoparticles encapsulating gemcitabine HCl (GM) and simvastatin (SV) were fabricated by double emulsion solvent evaporation method and optimized. Optimized nanoparticles showed a particle size of 258 ± 2.4 nm, polydispersity index of 0.32 ± 0.052, and zeta potential of -12.5 mV. The size and the morphology of the particles wee further confirmed by transmission electron microscopy (TEM) and scanning electron microscopy, respectively of the particles. The entrapment efficiency of GM and SV in the nanoparticles was 38.5 ± 4.5% and 72.2 ± 5.6%, respectively. The in vitro release profile was studied for 60 h and showed Higuchi release pattern. The cell toxicity was done using MTT assay and lower IC 50 was obtained with the nanoparticles as compared to the pure drug. The bioavailability of GM and SV in PLGA nanoparticles was enhanced by 1.4-fold and 1.3-fold respectively, compared to drug solution. The results revealed that co-delivery of GM and SV could be used for its oral delivery for the effective treatment of pancreatic cancer.

In recent years scientific community has drawn a great deal of attention towards understanding the enigma of cluster of differentiation-44 (CD44) in order to deliver therapeutic agents more selectively towards tumor tissues. Moreover, its over-expression in variety of solid tumors has attracted drug delivery researchers to target this receptor with nanomedicines. Conventional nanomedicines based on biodegradable polymers such as poly(lactide-co-glycolide) (PLGA) are often associated with insufficient cellular uptake by cancer cells, due to lack of active targeting moiety on their surface. Therefore, to address this limitation, CD44 targeted PLGA nanomedicines has gained considerable interest for enhancing the efficacy of chemotherapeutic agents. In this review, we have elaborately discussed the recent progress in the design and synthesis of CD44 targeted PLGA nanomedicines used to improve tumor-targeted drug delivery. We have also discussed strategies based on co-targeting of CD44 with other targeting moieties such as folic acid, human epidermal growth factor 2 (HER2), monoclonal antibodies using PLGA based nanomedicines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In recent years, research has focused on the development of smart nanocarriers that can respond to specific stimuli. Among the various stimuli-responsive platforms for cancer therapy, near-infrared (NIR) light (700-1000nm)-responsive nanocarriers have gained considerable interest because of their deeper tissue penetration capacity, precisely controlled drug release, and minimal damage towards normal tissues. In this review, we outline various therapeutic applications of NIR-responsive nanocarriers in drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), and bioimaging. We also highlight recent trends towards NIR-responsive combinatorial therapy and multistimuli-responsive nanocarriers for improving therapeutic outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The clinical application of betulinic acid (BA), a natural pentacyclic triterpenoid with promising antitumor activity, is hampered due to its extremely poor water solubility and relatively short half-life in the systemic circulation. In order to address these issues, herein, we developed betulinic acid loaded polylactide-co-glycolide- monomethoxy polyethylene glycol nanoparticles (PLGA-mPEG NPs). The PLGA-mPEG co-polymer was synthesized and characterized using NMR and FT-IR. BA loaded PLGA-mPEG NPs were prepared by an emulsion solvent evaporation method. The developed nanoparticles had a desirable particle size (∼147nm) and exhibited uniform spherical shape under transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The PLGA-mPEG NPs were able to decrease the uptake by macrophages (i.e. J774A.1 and Raw 264.7 cells) as compared to PLGA nanoparticles. In vitro cytotoxicity in MCF7 and PANC-1 cells demonstrated enhanced cytotoxicity of BA loaded PLGA-mPEG NPs as compared to free BA. The cellular uptake study in both the cell lines demonstrated time dependent uptake behavior. The enhanced cytotoxicity of BA NPs was also supported by increased cellular apoptosis, mitochondrial membrane potential loss, generation of high reactive oxygen species (ROS) and cell cycle arrest. Further, intravenous pharmacokinetics study revealed that BA loaded PLGA-mPEG NPs could prolong the circulation of BA and remarkably enhance half-life by ∼7.21 folds. Consequently, in vivo studies in Ehrlich tumor (solid) model following intravenous administration demonstrated superior antitumor efficacy of BA NPs as compared to native BA. Moreover, BA NPs treated Ehrlich tumor mice demonstrated no biochemical, hematological and histological toxicities. These findings collectively indicated that the BA loaded PLGA-mPEG NPs might serve as a promising nanocarrier for improved therapeutic efficacy of betulinic acid., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated for in vitro-in vivo performance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33 ± 7.50 nm, a PDI of 0.179 ± 0.05, and an entrapment efficiency of 56 ± 1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15 d. Additionally, an in vitro cytotoxicity testing as well as in vivo antitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Epirubicin (EPI) is a P-gp substrate antracycline analogue which elicits poor oral bioavailability. In the present work, EPI loaded poly-lactide-co-glycolic acid nanoparticles (PLGA-NPs) were prepared by double emulsion approach and superficially decorated with polyethylene glycol (EPI-PNPs) and mannosamine (EPI-MNPs). Average hydrodynamic particle size of EPI-PNPs and EPI-MNPs was found 248.63 ± 12.36 and 254.23 ± 15.16 nm, respectively. Cytotoxicity studies were performed against human breast adenocarcinoma cell lines (MCF-7) confirmed the superiority of EPI-PNPs and EPI-MNPs over free epirubicin solution (EPI-S). Further, confocal laser scanning microscopy (CLSM) and flow cytometric analysis (FACS) demonstrated enhanced drug uptake through EPI-PNPs and EPI-MNPs and elucidated dominance of caveolae mediated endocytosis for NPs uptake. Cellular transport conducted on human colon adenocarcinoma cell line (Caco-2) showed 2.45 and 3.17 folds higher permeability of EPI through EPI-PNPs and EPI-MNPs when compared with EPI-S (p<0.001) while permeability of EPI was found 5.23 and 5.67 folds higher across rat ileum, respectively. Furthermore, pharmacokinetic studies demonstrated 4.7 and 5.57 folds higher oral bioavailability through EPI-PNPs and EPI-MNPs when compared with EPI-S. In addition, both, EPI-PNPs and EMNPs showed tumor suppression comparable to indicated route (i.v. injection). EPI-MNPs showed 1.18 folds higher bioavailability and better tumor suppression than EPI-PNPs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A series of tryptophan-based peptides W1a, b-W4a, b, with diverse architectures were designed and synthesized. These tryptophan containing peptides can self-assemble to spherical particle. This self-assembled system was demonstrated to encapsulate rhodamine B and penetrate the cell membrane., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the feasibility of entrapping water-insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199 nm, while the SLNs prepared with palmitic acid had particle size in the range of 126-160 nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X-ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations.

Epirubicin (EPI) is an anthracycline antineoplastic agent, commercially available for intravenous administration only and its oral ingestion continues to remain a challenge. Present investigation is aimed at the development of poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) for oral bioavailability enhancement of epirubicin. Developed formulation revealed particle size, 235.3±15.12 nm, zeta potential, -27.5±0.7 mV and drug content (39.12±2.13 μg/mg), with spherical shape and smooth surface. Cytotoxicity studies conducted on human breast adenocarcinoma cell lines (MCF-7) confirmed the superiority of epirubicin loaded poly-lactic-co-glycolic acid nanoparticles (EPI-NPs) over free epirubicin solution (EPI-S). Further, flow cytometric analysis demonstrated improved drug uptake through EPI-NPs and elucidated the dominance of caveolae mediated endocytosis for nanoparticles uptake. Transport study accomplished on human colon adenocarcinoma cell line (Caco-2) showed 2.76 fold improvement in permeability for EPI-NPs as compared to EPI-S (p<0.001) whereas a 4.49 fold higher transport was observed on rat ileum; a 1.8 fold higher (p<0.01) in comparison to Caco-2 cell lines which confirms the significant role of Peyer's patches in absorption enhancement. Furthermore, in vivo pharmacokinetic studies also revealed 3.9 fold improvement in oral bioavailability of EPI through EPI-NPs. Henceforth, EPI-NPs is a promising approach to replace pre-existing intravenous therapy thus providing "patient care at home"., (Copyright © 2015. Published by Elsevier B.V.)

The dual drug loaded poly(dl-lactic-co-glycolic acid) (PLGA(1)) nanoparticles (TOP-TAM NPs(2)) concurrently delivering topotecan hydrochloride (TOP(3)) and tamoxifen citrate (TAM(4)) were developed to achieve synergism for the treatment of breast cancer by enhancing the permeation of TOP through the gut and the cells present in the breast. TAM acted as P-glycoprotein (P-gp(5)) inhibitor, reduced the side effects of individual drugs by reducing the dose. The NPs were prepared by double emulsion (w/o/w) method. The optimized TOP-TAM NPs were found to have smooth and spherical morphology by using SEM(6) and TEM(7) technique. Similarly size of nanoparticles was found to be 151.2 ± 1.6 nm with 0.147 ± 0.03 polydispersity index (PDI(8)). The percentage entrapment efficiency of 95.17 ± 3.57 and 57.77 ± 2.2 was found for TAM and TOP respectively. The lyophillized nanoparticles under DSC(9) showed amorphous nature of both TOP and TAM. In an in vitro release study the release of drugs from TOP-TAM NPs was found to follow the Higuchi pattern. The ex vivo gut permeation study revealed that the TAM enhanced the permeation of TOP and increased its bioavailability by 1.9 folds. The permeation and activity of combination of drugs were further confirmed by carrying out cell line studies on MCF-7 cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This study was aimed at understanding the role of alum in improving the immunogenicity of biodegradable polymer particle entrapped antigens. Presence of alum formed a fine network around PLA particles holding them together and promoted attachment of higher number of particles on macrophage surface for a considerable period of time. Use of alum lowered the burst release of the entrapped antigen from particles and thereafter also reduced the cumulative release of antigen from particles. Apart from this, PLA microparticles alone induced macrophages to release TNF-alpha similar to that induced by alum. However admixture of PLA particles and alum enhanced the secretion of TNF-alpha from 876pg/ml at 6h to 3500pg/ml at 24h which was higher than that induced by alum adsorbed TT. Immunization with admixture of antigen loaded polylactide (PLA) microparticles (2-8microm) and alum improved the antibody titers almost twice than that achieved from particle alone in experimental animals. Single point immunization with particle entrapped antigens and alum also elicited antibody titers comparable to two doses of alum adsorbed tetanus toxoid (TT) or diphtheria toxoid (DT). Our results suggest that presence of alum acts in multiple ways to improve the antibody titers of polymer particles entrapped antigens. Such co-operative adjuvant action of alum and polymer particles can be exploited to improve the immunogenicity of other antigens.

Large porous microparticles of PLGA entrapping insulin were prepared by solvent evaporation method and evaluated in diabetes induced rat for its efficacy in maintaining blood sugar level from a single oral dose. Incorporation of Eudragit L30D (0.03% w/v) in the external aqueous phase resulted in formation of pH responsive enteric coated polymer particles which release most of the entrapped insulin in alkaline pH. At acidic pH, release of insulin from uncoated PLGA microparticles and Eudragit L30D coated PLGA microparticles was 31.62 +/- 1.8% and 17.5 +/- 1.29%, respectively, for initial 30 min. However, in 24 h, in vitro released insulin from uncoated PLGA and Eudragit coated particles was 96.29 +/- 1.01% and 88.30 +/- 1%, respectively. Released insulin from composite polymer particles were mostly in monomer form without aggregation and was stable for a month at 37 degrees C. Oral administration of insulin loaded PLGA (50 : 50) and Eudragit L30D coated PLGA (50 : 50) microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxan induced diabetic rats resulted in 37.3 +/- 11% and 62.7 +/- 3.8% reduction in blood glucose level, respectively, in 2 h. This effect continued up to 24 h in the case of Eudragit L30D coated PLGA microparticles. Results demonstrate that use of stabilizers during PLGA particle formulation, large porous particle for quick release of insulin and coating with Eudragit L30D resulted in a novel oral formulation for once a day delivery of insulin.

Protein instability during microencapsulation has been one of the major hurdles of biodegradable polymer particles-based vaccine delivery systems. In the present work, effect of serum albumin, sucrose and sodium bicarbonate on surface morphology, entrapment efficiency, in vitro release and in vivo performance tetanus toxoid (TT) loaded PLA particles were investigated. Use of serum albumin as well as high concentration of protein antigen ( approximately 60mg/ml) helped in protecting the immunoreactivity of the antigen during primary emulsification step of particle formulation. Incorporation of sucrose in the internal aqueous phase led to the reduction in encapsulation efficiency of TT from 43.8+/-4.3% to 27.3+/-3.6% in PLA particles and resulted with formation of particles having irregular surface characteristics. Addition of sodium bicarbonate along with sucrose during primary emulsion led to slight improvement in encapsulation efficiency of TT (34.3+/-3.2%) but affected the in vivo performance in terms of serum anti-TT antibody titers from single point immunization. Restoration of osmotic balance by adding equivalent amount of sucrose in external aqueous phase helped in preventing multiple emulsion instability and subsequently improved the encapsulation efficiency of TT to 63.1+/-4.2%. Maximum entrapment efficiency of TT up to 69.2+/-5.1% was achieved when serum albumin, sucrose and sodium bicarbonate were used in internal aqueous phase and sucrose was used in the external aqueous phase. Polymer particles entrapping tetanus toxoid along with optimal stabilizers showed burst release of immunoreactive antigen (>40% in early period) and elicited high and sustained anti-TT antibody titers from single point intramuscular immunization. Anti-TT antibody titers were further enhanced upon immunization of admixture of PLA particles and alum. Choice and use of stabilizers during particle formulation thus need careful considerations not only to protect the immunoreactivity of the antigen, but also to produce stable, uniform particles for optimal in vivo performances.