title: A polymer-protein core-shell nanomedicine for inhibiting cancer migration followed by photo-triggered killing.
abstract: Migratory capacity of cancer plays a critical role in the process of metastasis. Aberrant focal adhesions activated by the phosphorylation of Src kinase enables cancer cells to anchor on its micro-environment and migrate towards biochemically favorable niche, causing metastasis. Effective blocking of the migratory capacity of cancer cells by inhibiting protein kinases and subsequent application of cytotoxic stress may provide better therapeutic outcome. Here, we report a novel core-shell nanomedicine that inhibits cancer migration by nano-shell and impart reactive oxygen stress by laser assisted photosensitization of nano-core. For this, we have optimized a polymer-protein nanoconstruct where a photosensitizer (5,10,15, 20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP) is loaded into poly(lactic-co-glycolic acid) (PLGA) nano-core and Src kinase inhibitor (dasatinib) is loaded into albumin nano-shell. The polymer-core was prepared by electrospray technique and albumin-shell was formed by alcohol coacervation. Transmission electron microscopy studies revealed the formation of - 80 nm sized nano-core decorated with - 10 nm size nano-shell. Successful incorporation of monomeric mTHPP in nano-core resulted improved photo-physical properties and singlet oxygen release under physiological conditions compared to free-mTHPP. Core-shell nanomedicine also showed dose and time dependent cellular uptake in U87MG glioma cells. Dasatinib released from nano-shell caused down regulation of phospho-Src leading to significant impairment of cancer migration and subsequent laser assisted photosensitization of nano-core resulted in the release of reactive oxygen stress leading to apoptosis of spatially confined cancer cells. In vivo studies on Wistar rats indicated the absence of any significant toxicity caused by the intravenous administration of nanomedicine. These results clearly show the advantage of core-shell nanomedicine mediated combinatorial approach for inhibiting important cancer signalling pathways togother with imparting cytotoxic stress.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Giridharan Loghanathan
authors.initials: GL
authors.lastname: Malarvizhi
authors.forename: Parwathy
authors.initials: P
authors.lastname: Chandran
authors.forename: Neha
authors.initials: N
authors.lastname: Gupta
authors.forename: Deepthy
authors.initials: D
authors.lastname: Menon
authors.forename: Dilip
authors.initials: D
authors.lastname: Panikar
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Nair
authors.forename: Manzoor
authors.initials: M
authors.lastname: Koyakutty
mesh_terms: D000418:Albumins / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D050997:Nanomedicine / Q000379:methods*; D017319:Photosensitizing Agents / Q000737:chemistry*; D010789:Phototherapy; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011166:Porphyrins / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; D004337:Drug Carriers; D017319:Photosensitizing Agents; D011166:Porphyrins; D011743:Pyrimidines; D013844:Thiazoles; C437342:tetra(3-hydroxyphenyl)porphine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000069439:Dasatinib