Anti-neuropilin 1 antibody Fab' fragment conjugated liposomal docetaxel for active targeting of tumours.
Neuropilin-1, a transmembrane receptor entailed in wide range of human tumour cell lines and diverse neoplasms, mediates the effects of VEGF and Semaphorins during the processes of cellular proliferation, survival and migration. In view of this, we had developed and evaluated in vitro and in vivo efficacy of anti-neuropilin-1 immunoliposomes against neuropilin-1 receptor expressing tumours. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. Functionalised PEGylated liposomes were prepared using post-insertion technique. Anti-neuropilin-1 immunoliposomes were prepared by covalently conjugating Fab' fragments of neuropilin-1 antibody to functionalised PEGylated liposomes via thioether linkage. In vivo evaluation of Taxotere and liposomal formulations was performed using intradermal tumour model to demonstrate anti-angiogenic and tumour regression ability. The modified Fab' fragments and immunoliposomes were found to be immunoreactive against A549 cells. Further, docetaxel loaded PEGylated liposomes and PEGylated immunoliposomes demonstrated higher in vitro cytotoxicity than Taxotere formulation at the same drug concentration and exposure time. The live imaging showed distinctive cellular uptake of functional immunoliposomes. Further, significant decrease in micro-blood vessel density and tumour volumes was observed using bio-engineered liposomes. The results clearly highlight the need to seek neuropilin-1 as one of the prime targets in developing an anti-angiogenic therapy.
Pharmacy Department, TIFAC Centre of Relevance and Excellence in New Drug Delivery Systems, G.H. Patel Pharmacy Building, The Maharaja Sayajirao University of Baroda , Fatehgunj, Vadodara, Gujarat , India .
Arehalli S
AS
Manjappa
Peeyush N
PN
Goel
Rajiv P
RP
Gude
Rayasa S
RS
Ramachandra Murthy
D000165:Acridine Orange; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D001692:Biological Transport; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004337:Drug Carriers; D016503:Drug Delivery Systems / Q000379:methods*; D004996:Ethidium; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D039942:Neuropilin-1 / Q000276:immunology*; D011092:Polyethylene Glycols / Q000737:chemistry; D013194:Staining and Labeling; D043823:Taxoids / Q000737:chemistry / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D043823:Taxoids; D039942:Neuropilin-1; D000077143:Docetaxel; D011092:Polyethylene Glycols; D004996:Ethidium; D000165:Acridine Orange
Angiogenesis; Fab′; docetaxel; fragments; immunoliposomes; intradermal tumour model; neuropilin-1 antibody