Cyclic-RGDfK peptide conjugated succinoyl-TPGS nanomicelles for targeted delivery of docetaxel to integrin receptor over-expressing angiogenic tumours.
Docetaxel (DTX) is an anticancer drug that is used alone and in combination with other drugs to treat tumours. However, it suffers from the drawback of non-specific cytotoxicity. To improve the therapeutic potential of DTX, we report the synthesis of cRGDfK peptide-conjugated succinoyl-TPGS (tocopheryl polyethylene glycol succinate) nanomicelles for targeted delivery of DTX. Among RGD (Arg-Gly-Asp) peptides, cRGDfK peptide shows specificity towards αvβ3 integrin receptors that are most commonly over-expressed in tumour cells. To cRGDfK peptide, succinoylated TPGS was synthesised and conjugated to cRGDfK peptide using a carbodiimide reaction. Peptide-conjugated DTX loaded nanomicelles (PDNM) displayed small particle size with a narrow distribution, controlled drug release and high physicochemical stability. Cytotoxicity, cellular uptake, apoptosis and anti-angiogenic comparisons of unconjugated nanomicelles to PDNM in DU145 human prostate cancer cells and HUVECs (Human Umblical Vein Endothelial Cells) clearly revealed the importance of the cRGDfK peptide in enhancing the drug delivery performance of nanomicelles.


BACKGROUND
Common to many chemotherapeutic agents for cancer, systemic toxicity remains a big concern. In this article, the authors attempted to address this issue by conjugating RGD based peptides to Docetaxel, which would target integrins expressed on tumor cell surface. The experimental data revealed enhanced drug delivery.
IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; School of Applied Sciences, RMIT University, Melbourne, Australia; Health Innovations Research Institute, RMIT University, Melbourne, Australia.
Hitesh
H
Kulhari
Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Deep
D
Pooja
Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
Shweta
S
Shrivastava
IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Srinivasa R
SR
Telukutala
Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Ayan K
AK
Barui
Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Chitta Ranjan
CR
Patra
Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Hyderabad, India.
Ganga Modi
GM
Naidu Vegi
Health Innovations Research Institute, RMIT University, Melbourne, Australia.
David J
DJ
Adams
Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India. Electronic address: sistla@iict.res.in.
Ramakrishna
R
Sistla
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008297:Male; D008823:Micelles; D049329:Nanostructures; D009389:Neovascularization, Pathologic; D010456:Peptides, Cyclic / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D016023:Integrins; D008823:Micelles; D010456:Peptides, Cyclic; D011956:Receptors, Cell Surface; D043823:Taxoids; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D014810:Vitamin E; D000077143:Docetaxel; D011092:Polyethylene Glycols; C014225:tocophersolan
Cytotoxicity; Docetaxel; Nanomicelles; Prostate cancer targeting; TPGS; cRGDfK