Yuan Zhang1, Xueqing Wang, Jiancheng Wang, Xuan Zhang, Qiang Zhang. 1. State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, People's Republic of China. sinoyuan11@gmail.com
Abstract
PURPOSE: Somatostatin analogue octreotide (OCT)-modified PEG-b-PLA micelles were constructed to bind to somatostatin receptors (SSTRs) overexpressed on tumor cells for enhanced intracellular drug delivery and improved therapeutic efficacy for malignant tumors. METHODS: Copolymers conjugated with octreotide (OCT-PEG₆₀₀₀-b-PLA₅₀₀₀) were synthesized. The fluorescent probe DiI or docetaxel (DTX)-loaded micelles with or without octreotide modification (OCT-PM-DiI, PM-DiI, OCT-PM-DTX and PM-DTX) were prepared, and their physiochemical properties, intracellular delivery in vitro or anti-tumor activity in vivo were evaluated, respectively. RESULTS: The CMC of OCT-PEG₆₀₀₀-b-PLA₅₀₀₀ was quite low (<10⁻⁶ mol/L). All micelles were less than 80 nm with spherical shape and high encapsulation efficiency. DTX molecules were well dispersed in the micelles without chemical interactions with the polymers. Flow cytometry and confocal microscopy results showed that OCT-PM-DiI enhanced intracellular delivery efficiency via receptor-mediated endocytosis in NCI-H446 cells; the optimal modification ratio of OCT on micelle surface was 5%. OCT-PM-DTX exhibited higher retardation of tumor growth after intravenous injections into xenograft NCI-H446 tumor model; octreotide-modified micelles did not show severe toxicity. CONCLUSIONS: SSTRs targeting micelles may serve as promising nanocarriers in tumor treatment for hydrophobic anticancer drugs, such as DTX.
PURPOSE: Somatostatin analogue octreotide (OCT)-modified PEG-b-PLA micelles were constructed to bind to somatostatin receptors (SSTRs) overexpressed on tumor cells for enhanced intracellular drug delivery and improved therapeutic efficacy for malignant tumors. METHODS:Copolymers conjugated with octreotide (OCT-PEG₆₀₀₀-b-PLA₅₀₀₀) were synthesized. The fluorescent probe DiI or docetaxel (DTX)-loaded micelles with or without octreotide modification (OCT-PM-DiI, PM-DiI, OCT-PM-DTX and PM-DTX) were prepared, and their physiochemical properties, intracellular delivery in vitro or anti-tumor activity in vivo were evaluated, respectively. RESULTS: The CMC of OCT-PEG₆₀₀₀-b-PLA₅₀₀₀ was quite low (<10⁻⁶ mol/L). All micelles were less than 80 nm with spherical shape and high encapsulation efficiency. DTX molecules were well dispersed in the micelles without chemical interactions with the polymers. Flow cytometry and confocal microscopy results showed that OCT-PM-DiI enhanced intracellular delivery efficiency via receptor-mediated endocytosis in NCI-H446 cells; the optimal modification ratio of OCT on micelle surface was 5%. OCT-PM-DTX exhibited higher retardation of tumor growth after intravenous injections into xenograft NCI-H446 tumor model; octreotide-modified micelles did not show severe toxicity. CONCLUSIONS: SSTRs targeting micelles may serve as promising nanocarriers in tumor treatment for hydrophobic anticancer drugs, such as DTX.
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