Engineered Hyaluronic Acid-Based Smart Nanoconjugates for Enhanced Intracellular Drug Delivery.

Bacterial polysaccharides can be easily modified to offer dual stimuli-responsive drug delivery systems with double targeting potential. In this research work, bacterial polysaccharides hyaluronic acid (HA) were functionalized with α-tocopherol polyethylene glycol succinate (TPGS) and cholic acid (CA) to form multifunctional polysaccharides nanoconjugates (TPGS-HA-CA). Smart nanoconjugates were synthesized by forming a redox-responsive disulfide bond, and it is composed of double targeting ligands. Doxorubicin (DOX) encapsulated smart nanoconjugates were exhibited an average size of 200 nm with a uniform core-shell structure. It serves the pH-responsive side chain modulation of TPGS-HA-CA, which affords a high degree of swelling at acidic pH. Under the pH 5.0 it shows 57% of release due to the side chain modulation of C-H/N-H. Polysaccharides nanoconjugates exhibited the double stimuli-responsive drug delivery by rapid disassembly of disulfide linkage, which exhibited 72% drug release (pH 5.0+GSH 10 mM). In cytotoxic studies, DOX@TPGS-HA-CA exhibited a higher cytotoxic effect compared to DOX. Hyaluronic acid functionalization with CA, TPGS increases cell internalization, and dual stimuli activity promotes more cell death. Overall, multifunctional polysaccharides hydrogel nanoconjugates is a prospective material that has great potential for targeting breast cancer therapy.

Self-assembled hydrogel nanocube for stimuli responsive drug delivery and tumor ablation by phototherapy against breast cancer.

The shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for the rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH and redox sensitivity for intracellular delivery of anticancer drugs and phototherapy. The cubical HA-DOP-CS-PEG networks with disulfide links are obtained by cross-linking HA-DOP-CS-PEG with cystamine. The pH-triggered hydrogel swelling/shrinkage was not only affords effective doxorubicin release. It also actively provides the endosomal/lysosomal escape, redox-triggered drug release. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione. Drug-loaded cube particles found to be 12% more cytotoxic. ICG and DOX-loaded hydrogel cubes demonstrate 90% cytotoxicity when incubated with MCF-7 cancer cells for 24 and 48 h, respectively. This approach integrates the advantages of pH sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for controlled delivery of therapeutics.

Sericin-chitosan doped maleate gellan gum nanocomposites for effective cell damage in Mycobacterium tuberculosis.

Polysaccharides are increasingly used as biodegradable nanocarrier to selectively deliver therapeutic agents to specific cells. In this study, maleate gellan gum (MA-GG) formed by addition of free radical polymerizable groups, which can be polymerized presence of acetone to design biodegradable three-dimensional networks, were synthesized by esterification. Natural silk sericin was grafted over the maleate gellan gum surface. Maleate Gellan Gum- Silk Sericin-Chitosan (MA-GG-SS-CS) nanocomposites loaded with rifampicin (RF) and pyrazinamide (PZA) to overcome the problems associated with Tuberculosis (TB) therapy. The pH responsive behavior of gellan gum nanocomposites was reposed by silk sericin and exhibited sustained release of 79% RF and 82% PZA for 120 h at pH 4.0. The designed formulations shows higher antimycobacterial activity and rapid delivery of drugs at TB infected macrophage. Nanomaterial effectively aggregated and internalized into the bacterial cells and MH-S cells. Dual drug release inside the cells makes damage in the cell membrane. Green nanocomposites studies pave the way for important use of macromolecules in pulmonary delivery TB drugs.

Sericin/RBA embedded gellan gum based smart nanosystem for pH responsive drug delivery.

Polysaccharides protein complex offers a green alternative to synthetic polymers in the drug delivery system. Sericin (SC), a natural protein, in combination with rice bran albumin (RBA) and gellan gum (GG) forms a green based protein polysaccharide complex. The sericin functionalized gellan gum-rice bran (SC-GG-RBA) nanocomposites were characterized by different characterization techniques. It shows their prominent ability in balancing the biocompatibility, stability, biodegradability, and functionality of nanocarriers. The nanocomposites exhibited spherical shape with core protein-polysaccharide structures, and the average size was about 218 nm. High amount of Doxorubicin (DOX) was encapsulated into SC-GG-RBA nanocomposites in order to investigate the effective drug release in acidic tumor environment. DOX of 84% was released in vitro condition after 120 h in pH 4.0. DOX loaded green nanocomposites shows IC50 5 µg/mL which was very low compared to free DOX of 9 µg/mL after treatment with MCF-7 cells. Only 42% of cells were survived after treatment with green nanocomposites. This was due to the effective uptake of nanomaterial by cancer cells and direct release of DOX in cytoplasmic region. Such high performance green nanocomposites have great potential in expanding the utilization of biomaterial from natural resources and development of sensible application in biomedical field.

Co-encapsulation of dual drug loaded in MLNPs: Implication on sustained drug release and effectively inducing apoptosis in oral carcinoma cells.

Combinations of natural bee wax flavones chrysin with a chemo drug have been exhibiting high potential with reduced adverse effect. To extend the synergistic effect of chrysin and improve the MLNPs (Multi Layer Nanoparticles) performance in drug release, layer-by-layer of poly [di(sodium carboxyphenoxy)phosphazene] (PDCPP) and poly (diallyldimethyl ammonium chloride) (PDADMAC) deposited on the CaCO3 nanoparticles (CCNPs) surface. The results suggest spherical MLNPs of 237 nm are formed with high drug loading content with enhanced cellular uptake. Under acidic conditions, multi layer structure effectively controls burst release, providing sustained drug release for long period. The combined effect of chrysin and cisplatin improved the cytotoxic potential of MLNPs at 25 µg.mL-1 concentration. Angiogenesis inhibitor chrysin activates reactive oxygen species (ROS) production and eventually leads to mitochondrial dysfunction. Furthermore, significant decreases of buccal pouch carcinoma in hamster model. Dual drug loaded MLNPs achieves 92% regressions of tumor volume as compared to cisplatin alone loaded MLNPs. In addition, Histopathology studies demonstrated the biocompatible effect of MLNPs on vital organs. This work provides a simple method to formulate multiple drugs in single nanosystem with high therapeutic efficacy on oral cancer.