PMID: 12751627May 20, 2003Paper

Correlation of subcellular compartmentalization of HPMA copolymer-Mce6 conjugates with chemotherapeutic activity in human ovarian carcinoma cells

Pharmaceutical Research
Monica TijerinaJ Kopecek

Abstract

Intracellular targets sensitive to oxidized damage generated by photodynamic therapy (PDT) utilizing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-mesochlorin e6 monoethylenediamine (Mce6) conjugates was explored to aid in the design of second generation PDT delivery systems. Low temperature, metabolic inhibitor, and nuclear localization sequences (NLS(FITC)) were used to achieve desired subcellular localization that was evaluated by confocal analysis and subcellular fractionation. Mce6 was bound to HPMA copolymer conjugates via non-degradable dipeptide linkers (P-GG-Mce6, P-NLS(FITC)-GG-Mce6) or lysosomally degradable tetrapeptide spacers (P-GFLG-Mce6, P-NLS(FITC)-GFLG-Mce6). Chemotherapeutic efficacy was assessed by the concentration that inhibited growth by 50% (IC50), cell associated drug concentration (CAD) and confocal microscopy. P-GFLG-Mce6 possessed enhanced chemotherapeutic activ ity compared to P-GG-Mce6 indicating enzymatically released Mce6 was more active than copolymer-bound Mce6. Lysosomes appeared less sensitive to photodamage as observed by a higher IC50. Nuclear-directed HPMA copolymer-Mce6 conjugates (P-NLS(FITC)-GG-Mce6, P-NLS(FITC)-GFLG-Mce6) possessed enhanced chemotherapeutic activity. However, cont...Continue Reading

Citations

Nov 4, 2008·Expert Opinion on Drug Delivery·Stéphane A SibaniRyan F Donnelly
May 7, 2011·Photochemical & Photobiological Sciences : Official Journal of the European Photochemistry Association and the European Society for Photobiology·Andrzej M Bugaj
Feb 21, 2013·Clinical Endoscopy·Il YoonYoung Key Shim
Jul 6, 2014·Chemistry : a European Journal·Tung-Sheng HsiehCheng-Chung Chang
Mar 21, 2014·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yen-Chih Lai, Cheng-Chung Chang
Aug 1, 2020·Advanced Drug Delivery Reviews·Jindřich Kopeček, Jiyuan Yang
Mar 17, 2020·International Journal of Pharmaceutics·Dandan XieYuan Huang
Feb 17, 2006·Journal of Medicinal Chemistry·Martha Sibrian-VazquezM Graça H Vicente
Jul 24, 2008·Molecular Pharmaceutics·Ayman KhdairJayanth Panyam
Aug 8, 2006·Molecular Pharmaceutics·Ludmila O CintezaParas N Prasad

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