PEG-PLGA- hybrid nanoparticles loaded with etoricoxib – phospholipid complex for effective treatment of inflammation in rat model

The aim of the present study was to increase the bioavailability of the etoricoxib by making PEG-PLGA-Hybrid nanoparticles using emulsion solvent evaporation method. Then the prepared nanoparticles were further characterised using TEM, particle size, PDI, zeta potential, encapsulation efficiency and drug release study. Lipid (Phospholipon 90-G) and drug thermal behaviour were studied using DSC, TGA. The results of optimised formulation of Particle size, PDI and zeta potential was found 216.6?±?4.0?nm, 0.24?±?0.19 and +36.3?±?1.9?mV. Encapsulation efficiency was found in the range of 77.15% w/v to 93.88% w/v. In-vivo study shows that the optimised formulation at a particular dose decreases the swelling index and number of writhes. Stability study indicated that the nanoparticles can be stored at a temperature of 4?±?2?°C/60?±?5% RH in well-closed container, away from heat and damp places. The prepared formulation has significantly increased the bioavailability of etoricoxib via oral administration.     

Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate

For folate-receptor-targeted anticancer therapy, docetaxel (DTX) nanoparticles (NPs) were produced employing polylactide-co-glycolide–polyethylene glycol–folate (PLGA–PEG–FOL) conjugate. The FOL-conjugated di-block copolymer was synthesized by coupling the PLGA–PEG–NH₂ di-block copolymer with an activated folic acid. It was expected that FOL moieties were exposed on the micellar surface.

The conjugates assisted in the formation of DTX NPs with an average size of 200 nm in diameter through an emulsification/solvent diffusion method. The FOL-targeted NPs showed a greater extent of intracellular uptake in FOL-receptor-positive cancer cells (SKOV3) in comparison with the non-targeted NPs, indicating that the FOL-receptor-mediated endocytosis mechanism could have a role in the cellular uptake of NPs. These results suggested that FOL-targeted DTX NPs could be a potentially useful delivery system for FOL-receptor-positive cancer cells.     

Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform

The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core–shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core–shell-type lipid–polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics.From the Clinical EditorThis comprehensive review covers the current applications of core–shell-type lipid–polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.     

Stealth lipid polymer hybrid nanoparticles loaded with rutin for effective brain delivery – comparative study with the gold standard (Tween 80): optimization,characterization and biodistribution

The blood–brain barrier is considered the leading physiological obstacle hindering the transport of neurotherapeutics to brain cells. The application of nanotechnology coupled with surfactant coating is one of the efficacious tactics overcoming this barrier. The aim of this study was to develop lipid polymer hybrid nanoparticles (LPHNPs), composed of a polymeric core and a phospholipid shell entangled, for the first time, with PEG-based surfactants (SAA) viz. TPGS or Solutol HS 15 in comparison with the gold standard Tween 80, aiming to enhance brain delivery and escape opsonization. LPHNPs were successfully prepared using modified single-step nanoprecipitation technique, loaded with the flavonoid rutin (RU), extracted from the flowers of Calendula officinalis L., and recently proved as a promising anti-Alzheimer. The effect of the critical process parameters (CPP) viz. PLGA amount, W_lecithin/W_PLGA ratio, and Tween 80 concentration on critical quality attributes (CQA); entrapment, size and size distribution, was statistically analyzed via design of experiments, and optimized using the desirability function. The optimized CPP were maintained while substituting Tween 80 with other PEG-SAA. All hybrid particles exhibited spherical shape with perceptible lipid shells. The biocompatibility of the prepared NPs was confirmed by hemolysis test. The pharmacokinetic assessments, post-intravenous administration to rats, revealed a significant higher RU bioavailability for NPs relative to drug solution. Biodistribution studies proved non-significant differences in RU accumulation within brain, but altered phagocytic uptake among various LPHNPs. The present study endorses the successful development of LPHNPs using PEG-SAA, and confirms the prospective applicability of TPGS and Solutol in enhancing brain delivery.     

Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability

Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid–phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid–phospholipid complex was verified through solubility studies.Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid–phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83–85 °C.The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA.     

PLGA nanoparticles loaded with the antileishmanial saponin β-aescin: factor influence study and in vitro efficacy evaluation

Colloidal carriers are known to improve the therapeutic index of the conventional drugs in the treatment of visceral leishmaniasis (VL) by decreasing their toxicity whilst maintaining or increasing therapeutic efficacy. This paper describes the development of poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the antileishmanial saponin β-aescin. NPs were prepared by the W/O/W emulsification solvent evaporation technique and the influence of five preparation parameters on the NPs’ size (Z_ave), zeta potential and entrapment efficiency (EE%) was investigated using a 2⁵⁻² fractional factorial design. Cytotoxicity of aescin, aescin-loaded and blank PLGA NPs was evaluated in J774 macrophages and non-phagocytic MRC-5 cells, whereas antileishmanial activity was determined in the Leishmania infantum ex vivo model. The developed PLGA NPs were monodispersed with Z_ave < 500 nm and exhibited negative zeta potentials. The process variables ‘surfactant primary emulsion’, ‘concentration aescin’ and ‘solvent evaporation rate’ had a positive effect on EE%. Addition of Tween^® 80 to the inner aqueous phase rendered the primary emulsion more stable, which in its turn led to better saponin entrapment. The selectivity index (SI) towards the supporting host macrophages increased from 4 to 18 by treating the cells with aescin-loaded NPs instead of free β-aescin. In conclusion, the in vitro results confirmed our hypothesis.     

Enhanced delivery of etoposide across the blood–brain barrier to restrain brain tumor growth using melanotransferrin antibody- and tamoxifen-conjugated solid lipid nanoparticles

Melanotransferrin antibody (MA) and tamoxifen (TX) were conjugated on etoposide (ETP)-entrapped solid lipid nanoparticles (ETP-SLNs) to target the blood–brain barrier (BBB) and glioblastom multiforme (GBM). MA- and TX-conjugated ETP-SLNs (MA–TX–ETP–SLNs) were used to infiltrate the BBB comprising a monolayer of human astrocyte-regulated human brain-microvascular endothelial cells (HBMECs) and to restrain the proliferation of malignant U87MG cells. TX-grafted ETP-SLNs (TX–ETP–SLNs) significantly enhanced the BBB permeability coefficient for ETP and raised the fluorescent intensity of calcein-AM when compared with ETP-SLNs. In addition, surface MA could increase the BBB permeability coefficient for ETP about twofold. The viability of HBMECs was higher than 86%, suggesting a high biocompatibility of MA–TX–ETP-SLNs. Moreover, the efficiency in antiproliferation against U87MG cells was in the order of MA–TX–ETP-SLNs > TX–ETP-SLNs > ETP-SLNs > SLNs. The capability of MA–TX–ETP-SLNs to target HBMECs and U87MG cells during internalization was verified by immunochemical staining of expressed melanotransferrin. MA–TX–ETP-SLNs can be a potent pharmacotherapy to deliver ETP across the BBB to GBM.     

Preparation and characterization of solidified oleanolic acid–phospholipid complex aiming to improve the dissolution of oleanolic acid

The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OA-PC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic acid and oleanolic acid–phospholipid complex. The process of OA-PC was optimized and the type and proportion of fumed silica were studied by dissolution text. The structures of the phospholipid complex and solidified powder were also characterized by differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. In the dissolution tests, OA from solidified powder was further released compared with that from pure OA and OA-PC in different kinds of dissolution media. These results suggest that the method of preparing solidified powder of oleanolic acid–phospholipid complex is suitable for enhancing the dissolution rate of OA and OA-PC.     

Development of noncytotoxic PLGA nanoparticles to improve the effect of a new inhibitor of p53–MDM2 interaction

One possible approach to overcome solubility complications and enhance the biological activity of drugs is their incorporation into drug delivery systems. Within this scope, several nanosphere and nanocapsule formulations of a new inhibitor of p53–MDM2 interaction (xanthone 1) were developed and their physicochemical properties analyzed. Through the investigation of the effect of several empty nanoparticles on the growth of MCF-7 cells, it was possible to observe that four out of five formulations were cytotoxic and that some correlations between the toxic potential of these polymeric nanoparticles and their properties/composition could be extrapolated. One empty formulation of nanocapsules developed by emulsification/solvent evaporation and containing PLGA, PVA and Mygliol^® 812 was found to be noncytotoxic to this cell line. The corresponding compound 1-loaded nanocapsules showed an incorporation efficiency of 77% and revealed to be more potent than the free drug against cell growth inhibition, which may be related to the enhancement in its intracellular delivery. In an integrative study, the intracellular uptake of nanocapsules was confirmed using fluorescent 6-coumarin and well as compound 1 release from nanocapsules. Overall, it was possible to enhance the effect of the hit inhibitor of p53–MDM2 interaction through the development of suitable noncytotoxic polymeric nanoparticles.     

Concanavalin A-conjugated poly(ethylene glycol)–poly(lactic acid) nanoparticles for intranasal drug delivery to the cervical lymph nodes

Abstract

Concanavalin A (ConA)-conjugated poly(ethylene glycol)–poly(lactic acid) nanoparticles (ConA-NPs) were prepared for targeted drug delivery to the cervical lymph nodes after intranasal administration. ConA, a lectin specifically binding to α-mannose and α-glucose, was covalently conjugated on NPs without loss of its carbohydrates binding bioactivity. In vitro cellular uptake experiment demonstrated that NPs could be uptaken by Calu-3 cells in a time- and concentration-dependent manner, and conjugation of ConA on NPs could significantly increase the rate and amount of cellular uptake. ConA-NP showed no obvious toxicity to Calu-3 cells in vitro or to the nasal cilia of rats in vivo. Compared with NPs without ConA, ConA-NP is more effective in targeting drugs to the deep cervical lymph nodes, as evidenced by 1.36–2.52 times increase of targeting efficiency, demonstrating that ConA-NP is a potential carrier for targeted drug delivery to the cervical lymph nodes via nasal route.     

Ratiometric delivery of two therapeutic candidates with inherently dissimilar physicochemical property through pH-sensitive core–shell nanoparticles targeting the heterogeneous tumor cells of glioma

Currently, combination drug therapy is one of the most effective approaches to glioma treatment. However, due to the inherent dissimilar pharmacokinetics of individual drugs and blood brain barriers, it was difficult for the concomitant drugs to simultaneously be delivered to glioma in an optimal dose ratio manner. Herein, a cationic micellar core (Cur-M) was first prepared from d-α-tocopherol-grafted-ε-polylysine polymer to encapsulate the hydrophobic curcumin, followed by dopamine-modified-poly-γ-glutamic acid polymer further deposited on its surface as a anion shell through pH-sensitive linkage to encapsulate the hydrophilic doxorubicin (DOX) hydrochloride. By controlling the combinational Cur/DOX molar ratio at 3:1, a pH-sensitive core–shell nanoparticle (PDCP-NP) was constructed to simultaneously target the cancer stem cells (CSCs) and the differentiated tumor cells. PDCP-NP exhibited a dynamic diameter of 160.8?nm and a zeta-potential of –30.5?mV, while its core–shell structure was further confirmed by XPS and TEM. The ratiometric delivery capability of PDCP-NP was confirmed by in vitro and in vivo studies, in comparison with the cocktail Cur/DOX solution. Meanwhile, the percentage of CSCs in tumors was significantly decreased from 4.16% to 0.95% after treatment with PDCP-NP. Overall, PDCP-NP may be a promising carrier for the combination therapy with drug candidates having dissimilar physicochemical properties.