ABSTRACT
Photo-Chemo combination therapy has been intensively investigated for treatment of cancers, especially multidrug resistance cancer. However, antagonistic interactions between chemo-drugs and photosensitizers are frequently reported, and drugs doses and treatment sequences have been changed to overcome the problems. We observed the antagonistic effect by a decrease in singlet oxygen generation from the photosensitizer when Dox was in close physical proximity. To control the distance between Dox and the photosensitizer, we developed a novel pH-sensitive poly ionomer complex system composed of PEG-PLL(-g-Ce6) [Chlorin e6 grafted poly(ethylene glycol)-poly(l-lysine)] and PEG-PLL(-g-DMA)-PLA [2,3-dimethylmaleic anhydride grafted poly(ethylene glycol)-poly(l-lysine)-poly(lactic acid)] and evaluated this system with regard to singlet oxygen generation and antiproliferative activity against MCF-7/Dox cells. Enhanced singlet oxygen generation and antiproliferative activities were observed in vitro and in vivo for the poly ionomer complex system compared to PEG-PLL(-g-Ce6)-PLA/Dox due to the change in distance between Dox and Ce6 in the PIC system under acidic conditions. Our results highlight the importance of interactions between co-loaded drugs in combination therapy, and provide new insights into design principles for tailor-made nanomedicine platforms.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Delayed-Action Preparations/chemistry , Doxorubicin/administration & dosage , Neoplasms/drug therapy , Photosensitizing Agents/administration & dosage , Porphyrins/administration & dosage , Animals , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/therapeutic use , Cell Proliferation/drug effects , Chlorophyllides , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Drug Resistance, Multiple/drug effects , Female , Humans , MCF-7 Cells , Mice, Inbred BALB C , Mice, Nude , Neoplasms/pathology , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Polyesters/chemistry , Polyethylene Glycols/chemistry , Polylysine/analogs & derivatives , Polylysine/chemistry , Porphyrins/pharmacology , Porphyrins/therapeutic useABSTRACT
BACKGROUND: Blending micellar systems of different types of polymers has been proposed as an efficient approach for tailor-made drug formulations. The lamellar structure of hydrophobic polymers may provide a high drug loading capacity, and hydrophilic polymers may provide good colloidal stability. METHODS: In this study, the anticancer model drug docetaxel was loaded onto a nanosized blending micellar system with two pluronics (L121/F127). To achieve increased antitumor activity, the cyclic arginine-glycine-aspartic acid tripeptide (cRGD) as an active tumor targeting ligand was conjugated to the blending system. RESULTS: The docetaxel-loaded Pluronic blending system exhibited a higher drug loading capacity than that of F127 and showed high colloidal stability with a spherical structure. cRGD conjugates demonstrated enhanced drug cellular uptake and anticancer activity against αvß3 integrin-overexpressing U87MG cancer cells. In vivo animal imaging also revealed that the prepared cRGD-conjugated nanoparticles effectively accumulated at the targeted tumor site through an active and passive targeting strategy. CONCLUSION: Accordingly, the prepared nanosized system shows potential as a tailor-made, active targeting, nanomedicinal platform for anticancer therapy. We believe that this novel nanoplatform will provide insights for advancement of tumor therapy.