title: 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.
authors: Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr Homi Bhabha Road, Pune - 411008, Maharashtra, India. jayakannan@iiserpune.ac.in.
authors: P S
authors: PS
authors: Pramod
authors: Ruchira
authors: R
authors: Shah
authors: Manickam
authors: M
authors: Jayakannan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival; D003911:Dextrans / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018613:Microscopy, Confocal; D050997:Nanomedicine; D011108:Polymers / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water / Q000737:chemistry
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D011108:Polymers; D011134:Polysaccharides; D014867:Water; D004317:Doxorubicin