The activity against Ehrlich's ascites tumors of doxorubicin contained in self assembled, cell receptor targeted nanoparticle with simultaneous oral delivery of the green tea polyphenol epigallocatechin-3-gallate.
Doxorubicin (DOX) is a well-known anticancer drug used for the treatment of a wide variety of cancers. However, undesired toxicity of DOX limits its uses. To address the issue of minimizing toxicity of DOX by making it targeted towards cancer cells, DOX was entrapped in self-assembled 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid (HDHA) nanoparticles. We hypothesized that by encapsulating the drug in biodegradable nanoparticles, its therapeutic efficacy would improve, if targeted against cancer cells. We synthesized cell receptor targeted, DOX loaded HDHA nanoparticles (NPs) and non-targeted DOX loaded O-hexadecylated dextran (HDD) nanoparticles (NPs) and characterized them for their entrapment efficiency, percent yield, drug load, surface morphology, particle size and in vitro drug release. The anticancer efficacy of DOX loaded HDHA-NPs was evaluated by measuring the changes in tumor volumes, tumor weights, and mean survival rate of Swiss albino mice grafted with Ehrlich's ascites carcinoma (EAC) cells. For this, the animals were given HDHA-DOX-NPs (1.5 mg/kg b.wt.) intravenously and a green tea polyphenol, Epigallocatechin-3-gallate (EGCG) (20 mg/kg b.wt.), orally through gavage. The targeted NP dose with EGCG significantly increased mean survival time of the animals and enhanced the therapeutic efficacy of the drug compared to the non-targeted NPs and free DOX. Further, we showed that these NPs (HDD and HDHA) were more active in the presence of EGCG than DOX alone in inducing apoptosis in EAC cells as evident by an increase in sub-G1 cells (percent), Annexin V positive cells and chromatin condensation along with the reduction in mitochondrial membrane potential (MMP). The study demonstrates that DOX loaded HDHA-NPs along with EGCG significantly inhibit the growth of EAC cells with ∼38-fold dose advantage compared to DOX alone and thus opens a new dimension in cancer chemotherapy.
CSIR-Indian Institute of Toxicology Research, Lucknow 226001, UP, India.
Lipika
L
Ray
Pradeep
P
Kumar
Kailash C
KC
Gupta
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000473:pathology*; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010316:Particle Size; D013056:Spectrophotometry, Ultraviolet; D013662:Tea / Q000737:chemistry*
D000970:Antineoplastic Agents; D013662:Tea; D004317:Doxorubicin; D002392:Catechin; C045651:epigallocatechin gallate