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cRGD/TAT Dual-Ligand Reversibly Cross-Linked Micelles Loaded with Docetaxel Penetrate Deeply into Tumor Tissue and Show High Antitumor Efficacy in Vivo
- Zhu, Yaqin, Zhang, Jian, Meng, Fenghua, Deng, Chao, Cheng, Ru, Feijen, Jan, Zhong, Zhiyuan
- ACS applied materials & interfaces 2017 v.9 no.41 pp. 35651-35663
- apoptosis, crosslinking, cytotoxicity, drugs, flow cytometry, lysosomes, micelles, neoplasm cells, peptides, polyethylene glycol
- The application of cell-penetrating peptides like TAT for in vivo targeted delivery is limited because the penetration behavior is not cell-specific. Herein, we designed cRGD and TAT comodified cross-linkable micelles (cRGD/TAT CMs), in which the TAT peptide was shielded by relatively long poly(ethylene glycol) (PEG) chains. Docetaxel (DTX)-loaded cRGD/TAT CMs were very stable with minimal drug leakage under physiological conditions, whereas rapid DTX release took place in a reductive environment. Flow cytometry showed that the cRGD/TAT CMs with molar ratios of 20% cRGD and 10% TAT (cRGD20/TAT10 CMs) were selectively and efficiently taken up by ανβ₃-overexpressing U87MG glioma cells, with 8.3-fold and 18.3-fold higher uptake than cRGD20 CMs and PEG CMs, respectively. DTX-loaded cRGD20/TAT10 CMs exhibited a high cytotoxicity in U87MG cells, leading to rapid apoptosis of the tumor cells. Uptake mechanism studies revealed that cRGD20/TAT10 CMs mainly employed the caveolae-mediated endocytotic pathway and efficiently escaped from the lysosomes. Notably, cRGD20/TAT10 CMs had a long circulating time of 6.25 h in vivo, due to cross-linking of the micelles and shielding of the TAT peptide. Moreover, DTX-loaded cRGD20/TAT10 CMs exhibited a significantly higher accumulation and deeper penetration in subcutaneous U87MG glioma tissue compared to cRGD20 CMs and PEG CMs, leading to superior antitumor efficacy in vivo. Therefore, this dual-ligand strategy provides an effective way to realize tumor-specific penetration and inhibition.