Vitamin B12 Grafted Layer-by-Layer Liposomes Bearing HBsAg Facilitate Oral Immunization: Effect of Modulated Biomechanical Properties.

Adhesion forces of nanoparticulate materials toward biological membrane are crucial for designing a delivery system for therapeutic molecules and vaccines. The present study aims to investigate the impact of surface roughness of the nanoparticulate system in oral delivery of antigen and its targeting to toward intestinal antigen presenting cells. To evaluate this hypothesis, layer-by-layer coated liposomes (LBL-Lipo) were fabricated using sodium alginate and Vitamin B12 conjugated Chitosan (VitB12-Chi) as anionic and cationic polyelectrolyte, respectively. Change in surface roughness was observed on changes in pH from gastric to intestinal conditions attributed to increase and decrease in charge density on VitB12-Chi. Surface roughness was measured in terms of root-mean-square measured by topographical analysis using atomic force microscopy. LBL-Lipo were further characterized for their size, zeta potential, and release behavior to evaluate the potential for oral vaccine delivery. In vitro cell uptake in macrophage cells (J-744) shows about 2- and 3.1-fold increased uptake of rough LBL-Lipo over smooth LBL-Lipo at 37 °C (endocytosis) and 4 °C (endocytosis inhibition) indicating improved biological interaction. Further in vivo immunization study revealed that prototype formulations were able to produce 4.8- and 3.3-fold higher IgG and IgA levels in serum and feces, respectively, in comparison to smooth LBL-Lipo.

Development of targeted 1,2-diacyl-sn-glycero-3-phospho-l-serine-coated gelatin nanoparticles loaded with amphotericin B for improved in vitro and in vivo effect in leishmaniasis.

OBJECTIVE: The principle objective of this study was to develop 1,2-diacyl-sn-glycero-3-phospho-l-serine (PS)-coated gelatin nanoparticles (GNPs) bearing amphotericin B (AmB) for specific targeting to the macrophages involved in visceral leishmaniasis (VL). METHOD: The two-step desolvation method has been used for the preparation of GNPs with AmB, which was further coated with PS (PS-AmB-GNPs). The targeting potential of it was compared with uncoated AmB-loaded GNPs (AmB-GNPs) for in vitro and in vivo macrophage uptake. RESULTS: The results of flow cytometric data revealed enhanced uptake of PS-AmB-GNPs in J774A.1 macrophage cell lines compared with AmB-GNPs. In vivo organ distribution studies in Wistar rats demonstrated a significantly higher extent of accumulation of PS-AmB-GNPs compared with AmB-GNPs in macrophage-rich organs, particularly in liver and spleen. The in vivo anti-leishmanial activity of plain AmB, AmB-GNPs and PS-AmB-GNPs was tested against VL in Leishmania donovani-infected hamsters. Highly significant anti-leishmanial activity (p < 0.05 compared with AmB-GNPs) was observed with PS-AmB-GNPs, causing 85.3 ± 7.89% inhibition of splenic parasitic burden. AmB-GNPs and plain AmB caused only 71.0 ± 3.87 and 50.5 ± 5.12% parasite inhibitions, respectively, in Leishmania-infected hamsters (p < 0.05 for PS-AmB-GNPs versus plain AmB and AmB-GNPs versus plain AmB). CONCLUSION: The objective of the preparation was achieved and high accumulation of AmB in liver and spleen has been found, which resulted in enhanced anti-leishmanial activity.

Development of doxorubicin loaded novel core shell structured nanocapsules for the intervention of visceral leishmaniasis.

The aim of this study was to develop novel nanoemuslion core loaded nanocapsules (NCs) with high payload of doxorubicin (DOX) and to assess its efficacy against Leishmania donovani. The low energy emulsification method was used to obtained nanoemulsion core as template, followed by stepwise addition of additional layer components protamine sulphate and sodium alginate. Zeta potential studies revealed that there was reversal in charge after each layering. NCs were characterized on the basis of size (340 nm) and entrapment efficiency (>80%). The drug release behaviour was studied by in vitro method. The NCs loaded with DOX (NCs-DOX) is completely internalized into macrophages showing improved efficacy (IC50 of formulation is almost ≤ 1.9-fold as compared to plain drug, p < 0.05) against intracellular amastigotes.

Exploiting 4-sulphate N-acetyl galactosamine decorated gelatin nanoparticles for effective targeting to professional phagocytes in vitro and in vivo.

The present study was focused on the development of surface modified gelatin nanoparticles (SGNPs) using novel ligand 4-sulfated N-acetyl galactosamine (4-SO(4)GalNAc) for specific targeting to macrophages. The gelatin has been modified with the potential targeting moiety 4-SO(4)GalNAc, which was further used for the preparation of modified nanoparticles. The nanoparticles have been prepared by two step desolvation method. The SGNPs and unmodified gelatin nanoparticles (GNPs) were loaded with doxorubicin (DxR) and its targeting potential was compared. Developed DxR-loaded SGNPs (DxR-SGNPs) were found to have negative zeta potential (-19.8 ± 0.22 mV) whereas DxR-loaded GNPs (DxR-GNPs) have the positive zeta potential of around +12.2 ± 0.36 mV. The mean particle size of DxR-SGNPs and DxR-GNPs was found to be 283 ± 7 and 134 ± 5 nm, respectively. Flow cytometric data confirmed the enhanced uptake of DxR-SGNPs in J774A.1 and PBMC when compared with DxR-GNPs. Intracellular localization studies indicate that the fluorescence intensity of DxR-SGNPs was significantly higher when compared to DxR-GNPs. DxR-SGNPs rendered significantly higher localization of DxR in liver and spleen as compared to DxR-GNPs after i.v. administration. The study stipulates that 4-SO(4)GalNAc assures for targeting resident macrophages.

Development of nanocapsules bearing doxorubicin for macrophage targeting through the phosphatidylserine ligand: a system for intervention in visceral leishmaniasis.

OBJECTIVES: The purpose of this study was to explore the applicability, targeting potential and drug delivery to specialized phagocytes via phosphatidylserine (PS)-specific ligand-anchored nanocapsules (NCs) bearing doxorubicin. METHODS: The layer-by-layer method was utilized to prepare NCs having a nanoemulsion core loaded with doxorubicin (NCs-DOX), which was further grafted with PS. PS-coated NCs (PS-NCs-DOX) were compared with NCs-DOX for in vitro targeting ability by studying uptake by macrophages, intracellular localization, in vivo pharmacokinetics and organ distribution studies. The in vivo antileishmanial activity of free doxorubicin, NCs-DOX and PS-NCs-DOX was tested against visceral leishmaniasis in Leishmania donovani-infected hamsters. RESULTS: Flow cytometric data revealed 1.75-fold enhanced uptake of PS-NCs-DOX in J774A.1 macrophage cell lines compared with NCs-DOX. In vivo organ distribution studies in Wistar rats demonstrated a significantly higher extent of accumulation of PS-NCs-DOX compared with NCs-DOX in macrophage-rich organs, particularly in liver and spleen. Highly significant antileishmanial activity (P < 0.05 compared with NCs) was observed with PS-NCs-DOX, causing 85.23% ±â€Š4.49% inhibition of splenic parasitic burden. NCs-DOX and free doxorubicin caused only 72.88% ±â€Š3.87% and 42.85% ±â€Š2.11% parasite inhibition, respectively, in Leishmania-infected hamsters (P < 0.01 for PS-NCs-DOX versus free doxorubicin and NCs-DOX versus free doxorubicin). CONCLUSIONS: We conclude that the PS targeting moiety can provide a new insight for efficient drug delivery to specialized macrophages and thus may be developed for effective use in macrophage-specific delivery systems, especially for leishmaniasis.

Industrial perspective of gastroretentive drug delivery systems: physicochemical, biopharmaceutical, technological and regulatory consideration.

INTRODUCTION: Gastroretentive drug delivery systems (GRDDS) can overcome drawbacks associated with oral drug delivery, by defeating natural physiological principles. Various gastroretentive technologies have been developed in the past, but few of them achieved success on the market. AREAS COVERED: This review is focused on the key concepts required to make a high-quality drug product available in a timely and economical manner. EXPERT OPINION: Pharmacotherapy of various disease states can be amended by drug repurposing through GRDDS. Assessment of the effect of the fed and fasted condition on product performance should be necessary during initial development phases. Dual working technology would be a possible way to overcome drawbacks associated with different GRDDS. Before development of a drug product, the principles of scale up and process validation must be considered to improve the quality and market availability of GRDDS. Knowledge of all regulatory aspects will help to deliver a product to the market within a reasonable timeframe and in a cost-effective manner.

Gastroretentive dosage forms: a review with special emphasis on floating drug delivery systems.

In the present era, gastroretentive dosage forms (GRDF) receive great attention because they can improve the performance of controlled release systems. An optimum GRDF system can be defined as a system which retains in the stomach for a sufficient time interval against all the physiological barriers, releases active moiety in a controlled manner, and finally is easily metabolized in the body. Physiological barriers like gastric motility and gastric retention time (GRT) act as obstacles in developing an efficient GRDF. Gastroretention can be achieved by developing different systems like high density systems, floating drug delivery systems (FDDS), mucoadhesive systems, expandable systems, superporous systems, and magnetic systems. All these systems have their own merits and demerits. This review focused on the various aspects useful in development of GRDF including the current trends and advancements.

Emerging trend in nano-engineered polyelectrolyte-based surrogate carriers for delivery of bioactives.

IMPORTANCE OF THE FIELD: In recent decades a new colloidal drug delivery system based on layer-by-layer (LbL) technology has emerged, which offers promising means of delivering bioactive agents, specifically biological macromolecules including peptides and DNA. Nano-engineered capsules specifically fabricated from biocompatible and biodegradable polyelectrolytes (PEs) can provide a better option for encapsulation of cells thereby protecting cells from immunological molecules in the body, and their selective permeability can ensure the survival of encapsulated cells. AREAS COVERED IN THIS REVIEW: This review encompasses a strategic approach to fabricate nano-engineered microcapsules through meticulous selection of polyelectrolytes and core materials based on LbL technology. The content of the article provides evidence for its wide array of applications in medical therapeutics, as indicated by the quantity of research and patents in this area. Recent developments and approaches for tuning drug release, biocompatibility and cellular interaction are discussed thoroughly. WHAT THE READER WILL GAIN: This review aims to provide an overview on the development of LbL capsules with specific orientation towards drug and macromolecular delivery and its integration with other drug delivery systems, such as liposomes. TAKE HOME MESSAGE: Selection of PEs for the fabrication of LbL microcapsules has a profound effect on stability, drug release, biocompatibility and encapsulation efficacy. The release can be easily modulated by varying different physicochemical as well as physiological conditions. Scale-up approaches for the fabrication of LbL microcapsules by means of automation must be considered to improve the possibility of application of LbL microcapsules on a large scale.

Uptake of biodegradable gel-assisted LBL nanomatrix by Leishmania donovani-infected macrophages.

The aim of this study was to develop novel gel-assisted layer-by-layer (LBL) nanomatrix with high payload of doxorubicin (DOX) and to assess its efficacy against Leishmania donovani. The biodegradable LBL nanomatrix was fabricated using LBL technique using polyions (protamine and sodium alginate) on decomposable core. The developed system was characterized in vitro in terms of layer-by-layer growth and payload efficiency. The efficacy of optimized formulations was evaluated against L. donovani strain in terms of inhibitory concentration (IC50). Uptake studies by infected macrophages were investigated both qualitatively and quantitatively using fluorescence microscopy and flow cytometry. The autogelling property subsequent to core removal inside the nanomatrix resulted in high payload efficiency of DOX (i.e., >70%). The reversal in charge followed the same trend with additional layers, and the magnitude of the charge remained constant up to five complete bilayers of polyions. The DOX can be effectively encapsulated, delivered, and subsequently taken up by L. donovani-infected macrophage cells. The matrix is completely internalized into macrophages showing improved efficacy (IC50 of formulation is almost