Inactivation of harmful tumour-associated proteolysis by nanoparticulate system.
The primary aim in cancer therapy is to deliver anti-cancer drugs to their specific molecular targets in the tumour. Here we present a system composed of poly(d,l-lactide-co-glycolide) nanoparticles, cytokeratin specific monoclonal antibody and cystatin, a potent protease inhibitor, that can neutralize the excessive proteolytic activity associated with the invasive and metastatic potential of breast tumour cells. The antibody provides specific targeting of the delivery system to invasive breast epithelial cells and, additionally, prevents the generation of plasmin, a central extracellular protease involved in malignant progression. Polymeric nanoparticles rapidly enter the targeted cells and release the inhibitor cargo within the endosomes/lysosomes. The inhibitor is capable to inactivate lysosomal cysteine proteases, in particular cathepsin B, which is involved in the degradation of extracellular matrix inside the tumour cells. Our approach, which combines nanoparticulate delivery system with the inhibitory potential against extracellular and intracellular proteases, may improve the efficacy of therapy in patients with breast tumours compared to the application of individual protease inhibitors.
Kos
Janko
J
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, SI-1000 Ljubljana, Slovenia. janko.kos@ffa.uni-lj.si
Obermajer
Natasa
N
Doljak
Bojan
B
Kocbek
Petra
P
Kristl
Julijana
J
D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D000918:Antibody Specificity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D018938:Caco-2 Cells; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D002448:Cell Adhesion; D018920:Coculture Techniques; D015891:Cystatins / Q000008:administration & dosage* / Q000737:chemistry; D004306:Dose-Response Relationship, Immunologic; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D005260:Female; D006016:Glycolates / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D007633:Keratins / Q000276:immunology* / Q000378:metabolism; D019344:Lactic Acid; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010958:Plasminogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013499:Surface Properties / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015891:Cystatins; D004337:Drug Carriers; D006016:Glycolates; D018796:Immunoconjugates; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007633:Keratins; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator; D002401:Cathepsin B