ABSTRACT
BACKGROUND: The combination of multiple chemotherapeutics has been used in the clinic for enhanced cancer chemotherapy, however, frequent relapse, chemo-resistance and side effects remains therapeutic hurdles. Thus, the development of co-delivery system with enhanced targeting and synergistic different modal treatments has been proposed as promising strategies for intensive improvement of the therapeutic outcomes. RESULTS: We fabricated a nanocarrier based on gold nanorods (Au NRs), cRGD peptide-modified and multi-stimuli-responsive paclitaxel (PTX) and curcumin (CUR) release for synergistic anticancer effect and chemo-photothermal therapy (PTX/CUR/Au NRs@cRGD). The specific banding of cRGD to αvß3 integrin receptor on the tumor cell surfaces facilitated the endocytosis of PTX/CUR/Au NRs@cRGD, and the near-infrared ray (NIR) further enhanced the drug release and chemotherapeutical efficiency. Compared to single drug, single model treatment or undecorated-PTX/CUR/Au NRs, the PTX/CUR/Au NRs@cRGD with a mild NIR showed significantly enhanced apoptosis and S phase arrest in three cancer cell lines in vitro, and improved drug accumulation in tumor sites as well as tumor growth inhibition in vivo. CONCLUSIONS: The tumor targeted chemo-photothermal therapy with the synergistic effect of dual drugs provided a versatile strategy for precise cancer therapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Curcumin/administration & dosage , Drug Carriers/chemistry , Drug Liberation , Gold/chemistry , Nanotubes/chemistry , Paclitaxel/administration & dosage , A549 Cells , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Survival/drug effects , Curcumin/chemistry , Hep G2 Cells , Humans , Infrared Rays , Integrin alphaVbeta3/metabolism , KB Cells , Mice, Inbred BALB C , Paclitaxel/chemistry , Particle Size , Peptides, Cyclic/metabolism , Phototherapy/methods , Surface PropertiesABSTRACT
In recent decades, the development of novel photorelated nanomedicines as precise cancer nanotheranostics has received extensive attention. However, strategies aimed at integrating various stimuli-responsive multimodal therapies are needed. Herein, we developed a novel system for combined plasmonic photothermal therapy (PPTT) and chemotherapy using the tumor microenvironment and near-infrared (NIR)-responsive gold nanorod-drug conjugates (Au NR@Curcumin). To synthesize this conjugate, the alkanethiol aliphatic acid (11-mercaptoundecanoic acid, MUA) group was covalently linked to curcumin via an ester bond. MUA-curcumin conjugates and thiol-end-functionalized PEG were used to replace cetyltrimethylammonium bromide (CTAB) while modifying the surface of the Au NRs. The size, zeta potential and shape were measured to characterize Au NR@Curcumin. The release of curcumin from Au NR@Curcumin was achieved by the cleavage of the esterase-labile ester bond in the tumor microenvironment which was enriched in esterase. Under NIR irradiation, the release of curcumin from Au NR@Curcumin was accelerated, caused by the excellent photothermal effect of the Au NRs. The antitumor effects of Au NR@Curcumin were tested on A549 human lung cancer cells, KB human oral epidermoid carcinoma cells and HepG2 human liver carcinoma cells. The ability of the nanosystem to efficiently control the drug release responding to NIR laser irradiation and act as an outstanding hyperthermia agent was demonstrated. The systematic mechanistic elucidation of the tumor cell killing effect is achieved by inducing apoptosis and the arrest of the cell cycle in the treated cells. The combination of photothermal therapy and chemotherapy using the compact Au NR@Curcumin system showed a strong in vivo anticancer effect superior to that of either of the two treatments alone due to a synergistic effect. These results suggest that Au NR@Curcumin is a novel and promising photoablation agent that may be used for cancer nanotheranostics.
