Development of AE147 Peptide-Conjugated Nanocarriers for Targeting uPAR-Overexpressing Cancer Cells.

PURPOSE: An AE147 peptide-conjugated nanocarrier based on PEGylated liposomes was developed in order to target the metastatic tumors overexpressing urokinase-type plasminogen activator receptor (uPAR), which cancer progression via uPA signaling. Therefore, the AE147 peptide-conjugated nanocarrier system may hold the potential for active targeting of metastatic tumors. METHODS: The AE147 peptide, an antagonist of uPAR, was conjugated to the PEGylated liposomes for targeting metastatic tumors overexpressing uPAR. Docetaxel (DTX), an anticancer drug, was incorporated into the nanocarriers. The structure of the AE147-conjugated nanocarrier, its physicochemical properties, and in vivo biodistribution were evaluated. RESULTS: The DTX-loaded nanocarrier showed a spherical structure, a high drug-loading capacity, and a high colloidal stability. Drug carrying AE147 conjugates were actively taken up by the uPAR-overexpressing MDA-MB-231 cancer cells. In vivo animal imaging confirmed that the AE147-conjugated nanoparticles effectively accumulated at the sites of tumor metastasis. CONCLUSION: The AE147-nanocarrier showed potential for targeting metastatic tumor cells overexpressing uPAR and as a nanomedicine platform for theragnosis applications. These results suggest that this novel nano-platform will facilitate further advancements in cancer therapy.

Principles and applications of nanomaterial-based hyperthermia in cancer therapy.

Over the past few decades, hyperthermia therapy (HTT) has become one of the most promising strategies to treat cancer. HTT has been applied with nanotechnology to overcome drawbacks such as non-selectivity and invasiveness and to maximize therapeutic efficacy. The high temperature of HTT induces protein denaturation that leads to apoptosis or necrosis. It can also enhance the effects of other cancer therapies because heat-damaged tissues reduce radioresistance and help accumulate anticancer drugs. Gold nanoparticles and superparamagnetic iron oxide with different energy sources are commonly used as hyperthermia agents. New types of nanoparticles such as those whose surface is coated with several polymers and those modified with targeting moieties have been studied as novel HTT agents. In this review, we introduce principles and applications of nanotechnology-based HTT using gold nanoparticles and superparamagnetic iron oxide.

Co-delivery of D-(KLAKLAK)2 Peptide and Chlorin e6 using a Liposomal Complex for Synergistic Cancer Therapy.

Nanotechnology-based photo-chemo combination therapy has been extensively investigated to improve therapeutic outcomes in anticancer treatment. Specifically, with the help of a singlet oxygen generated by the photosensitizer, the endocytosed nanoparticles are allowed to escape from the endosomal compartment, which is currently an obstacle in nanotechnology-based anticancer therapy. In this study, a liposomal complex system (Lipo (Pep, Ce6)), composed of a chlorin e6-conjugated di-block copolymer (PEG-PLL(-g-Ce6)) and a D-(KLAKLAK)2 peptide loading liposome (Lipo (Pep)), was developed and evaluated for its anticancer activity. Due to the membrane lytic ability of the D-(KLAKLAK)2 peptide and the membrane disruptive effect of the singlet oxygen generated from chlorin e6, Lipo (Pep, Ce6) accelerated the disruption of the endosomal compartment, and exhibited strong synergistic anticancer activity in vitro. The prepared liposomal complex system could potentially maximize the efficacy of the nanotechnology-based photo-chemo combination therapy, and can be regarded as a novel, versatile strategy in advanced tumor therapy.

A nano-complex system to overcome antagonistic photo-chemo combination cancer therapy.

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.

Cyclic RGD-conjugated Pluronic® blending system for active, targeted drug delivery.

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.