Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells

Abstract

The present work reports the development of pH and enzyme dual responsive polysaccharide vesicular nano-scaffolds for the administration of doxorubicin via physical loading and polymer-drug conjugation to breast cancer cells. Dextran was suitably modified with a renewable resource 3-pentadecyl phenol unit through imine and aliphatic ester chemical linkages that acted as pH and esterase enzyme stimuli, respectively. These dual responsive polysaccharide derivatives self-organized into 200 ± 10 nm diameter nano-vesicles in water. The water soluble anticancer drug doxorubicin (DOX·HCl) was encapsulated in the hydrophilic pocket to produce core-loaded polysaccharide vesicles whereas chemical conjugation produced DOX anchored at the hydrophobic layer of the dextran nano-vesicles. In vitro studies revealed that about 70-80% of the drug was retained under circulatory conditions at pH = 7.4 and 37 °C. At a low pH of 6.0 to 5.0 and in the presence of esterase; both imine and ester linkages were cleaved instantaneously to release 100% of the loaded drugs. Cytotoxicity assays on Wild Type Mouse Embryonic Fibroblasts (WTMEFs) confirmed the non-toxicity of the newly developed dextran derivatives at up to 500 μg mL(-1) in PBS. MTT assays on fibroblast cells revealed that DOX·HCl loaded nano-vesicles exhibited better killing abilities than DOX conjugated polymer nano-vesicles. Both DOX loaded and DOX conjugated nano-vesicles were found to show significant killing in breast cancer cells (MCF 7). Confocal microscopy images confirmed the uptake of DOX loaded (or conjugated) nano-vesicles by cells compared to free DOX. Thus, the newly developed pH and enzyme dual responsive polysaccharide vesicular assemblies are potential drug vectors for the administration of DOX in both loaded and chemically conjugated forms for the efficient killing of breast cancer cells.

Core–shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells

“…Similar results were also observed for the reaction with cysteine (details are given in SF 9). [39][40][41] Amount of cisplatin released were monitored using OPD assay. From figures 7c, it was very clear that the free cisplatin reacted with these thiol species and produced Pt-S bond.…”

“…37 We and other research groups had earlier reported polysaccharide vesicles, [38][39][40] amphiphilic dendrons [41][42] and block copolymer assemblies 43 having enzyme-responsiveness for delivering anticancer drug molecules such as doxorubicin and camptothecin. 37 We and other research groups had earlier reported polysaccharide vesicles, [38][39][40] amphiphilic dendrons [41][42] and block copolymer assemblies 43 having enzyme-responsiveness for delivering anticancer drug molecules such as doxorubicin and camptothecin.…”

Real-Time Drug Release Analysis of Enzyme and pH Responsive Polysaccharide Nanovesicles

“…Detailed cellular uptake studies were done earlier to quantify the fluorescent intensity of the Rh-B loaded vesicles in normal cells (wild type mouse embryonic fibroblasts, WT-MEFs), breast cancer cells (MCF-7), and colon cancer cells (DLD-1). 27 The Rh-B vesicular particles were found to be stable and they were not found to affect both normal and cancer cells even though differences exist at the microlevel in The Journal of Physical Chemistry B Article these cell types at their intracellular compartments. Thus, the significant difference in lifetime of Rh-B in free and encapsulated form can be utilized for studying the release rate from vesicles.…”

“…These vesicular structures were characterized by electron microscopy, atomic force microscopy, and dynamic and static light scattering methods, and these details were reported elsewhere. 25,27 A schematic representation of DOX and Rh-B loading into vesicles (see Figure 2a) . This indicated that the steady state absorbance and emission spectroscopic methods were not able to distinguish between the free drug in solution and drug encapsulated in vesicles.…”

A review of solute encapsulating nanoparticles used as delivery systems with emphasis on branched amphipathic peptide capsules

“…Dextran, chitin, chitosan and their derivatives have been investigated for their use as drug carriers. Most of the vesicles in this category are modified polysaccharides adducted with either small (trimethyl-) 141,142 or larger (3-pentadecylphenol-) 143,144 hydrophobic groups to render them amphipathic. Chitosan derived polymer vesicles are the most studied in this category.…”