Formulation and characterization of polyester/polycarbonate nanoparticles for delivery of a novel microtubule destabilizing agent.
OBJECTIVE
Since our newly synthesized potent 5-indolyl derivative, (2-(1 H-Indol-5-yl) thiazol-4-yl) 3, 4, 5-trimethoxyphenyl methanone (LY293), to treat resistant melanoma was hydrophobic, our objective was to synthesize a biodegradable copolymer for formulating this drug into nanoparticles and to determine its anticancer activity and mechanism of action.


METHODS
Methoxy poly (ethylene glycol)-b-poly (carbonate-co-lactide) [mPEG-b-P (CB-co-LA)] was synthesized for formulating LY293 into nanoparticles by o/w emulsification and stabilization by solvent evaporation. Particle size, drug release profile, in vitro efficacy in multiple melanoma cells, and mechanism of action of drug-loaded nanoparticles were determined.


RESULTS
LY293-loaded nanoparticles with 170 nm mean size and 2.2 and 4.16% drug loading efficiently inhibited proliferation of A375 and B16F10 cells with IC(50) of 12.5 nM and 25 nM, respectively. LY293 circumvented multidrug resistance and inhibited proliferation of Pgp overexpressing MDA-MB435/LCC6 MDR1 melanoma cells. Upon treatment with LY293-loaded nanoparticles, A375 cells underwent cell cycle arrest in G2/M phase and apoptotic cell death. Immunofluorescence images showed inhibition of tubulin polymerization after treatment with LY293.


CONCLUSIONS
LY293-loaded mPEG-b-P (CB-co-LA) nanoparticles showed excellent efficacy and induced apoptosis in melanoma cells. These polyester/polycarbonate-based nanoparticles provided an excellent platform to deliver different poorly soluble drugs to melanoma.
Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, 19 South Manassas St., Memphis, Tennessee 38103, USA.
Vaibhav
V
Mundra
Yan
Y
Lu
Michael
M
Danquah
Wei
W
Li
Duane D
DD
Miller
Ram I
RI
Mahato
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D018432:Drug Resistance, Multiple / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011076:Polycarboxylate Cement / Q000737:chemistry*; D011091:Polyesters / Q000737:chemistry*; D058105:Polymerization / Q000187:drug effects; D011108:Polymers / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
C000599461:2-(1H-indol-5-yl)thiazol-4-yl) 3,4,5-trimethoxyphenyl methanone; D000970:Antineoplastic Agents; D007211:Indoles; D011076:Polycarboxylate Cement; D011091:Polyesters; D011108:Polymers; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; C005506:polycarbonate