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Photo and redox dual responsive reversibly cross-linked nanocarrier for efficient tumor-targeted drug delivery.

ABSTRACT: To develop a feasible and efficient nanocarrier for potential clinical application, a series of photo and redox dual responsive reversibly cross-linked micelles have been developed for the targeted anticancer drug delivery. The nanocarrier can be cross-linked efficiently via a clean, efficient, and controllable coumarin photodimerization within the nanocarrier, which simplify the formulation process and quality control prior clinical use and improve the in vivo stability for tumor targeting. At the same time, cross-linking of nanocarrier could be cleaved via the responsiveness of the built-in disulfide cross-linkage to the redox tumor microenvironment for on-demand drug release. Coumarin and disulfide bond was introduced into a linear-dendritic copolymer (named as telodendrimer) precisely via peptide chemistry. The engineered nanocarrier possesses good drug loading capacity and stability, and exhibits a safer profile as well as similar anticancer effects compared with free drug in cell culture. The in vivo and ex vivo small animal imaging revealed the preferred tumor accumulation and the prolonged tumor residency of the payload delivered by the cross-linked micelles compared to the non-cross-linked micelles and free drug surrogate because of the increased stability.

SUBMITTER: Shao Y

PROVIDER: S-EPMC4094256 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Photo and redox dual responsive reversibly cross-linked nanocarrier for efficient tumor-targeted drug delivery.

Shao Yu Y Shi Changying C Xu Gaofei G Guo DanDan D Luo Juntao J

ACS applied materials & interfaces 20140625 13

To develop a feasible and efficient nanocarrier for potential clinical application, a series of photo and redox dual responsive reversibly cross-linked micelles have been developed for the targeted anticancer drug delivery. The nanocarrier can be cross-linked efficiently via a clean, efficient, and controllable coumarin photodimerization within the nanocarrier, which simplify the formulation process and quality control prior clinical use and improve the in vivo stability for tumor targeting. At ...[more]

PMID: 24921150

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Project description:Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future.

Dataset Information

Photo and redox dual responsive reversibly cross-linked nanocarrier for efficient tumor-targeted drug delivery.

Publications

Photo and redox dual responsive reversibly cross-linked nanocarrier for efficient tumor-targeted drug delivery.

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