Design of Multifunctional Liposomal Nanocarriers for Folate Receptor-Specific Intracellular Drug Delivery

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• 作者：Min Hyung Kang ; Hyun Joon Yoo ; Yie Hyuk Kwon ; Ho Yub Yoon ; Sang Gon Lee ; Sung Rae Kim ; Dong Woo Yeom ; Myung Joo Kang ; Young Wook Choi
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：December 7, 2015
• 年：2015
• 卷：12
• 期：12
• 页码：4200-4213
• 全文大小：715K
• ISSN：1543-8392

文摘

As a novel carrier for folate receptor (FR)-targeted intracellular delivery, we designed two types of targetable liposomal systems using Pep-1 peptide (Pep1) and folic acid as a cell-penetrating peptide (CPP) and target molecule, respectively. Folate-linked Pep1 (Fol-Pep1) was synthesized by solid phase peptide synthesis (SPPS) and verified using <sup>1sup>H NMR and far-ultraviolet (UV) circular dichroism (CD). The chimeric ligand (Fol-Pep1)-modified liposome (cF-P-L) was prepared by coupling Fol-Pep1 to maleimide-derivatized liposomes at various ratios. The dual ligand (folate and Pep1)-modified liposome (dF/P-L) was prepared by separately attaching both ligands to the liposomal surface via a short (PEG<sub>2000sub>) or long (PEG<sub>3400sub>) linker. The physical and conformational characteristics including vesicle size, zeta potential, and the number of conjugated ligands were determined. Intracellular uptake specificities of various fluorescent probe-containing cF-P-L and dF/P-L systems were assessed using FR-positive HeLa and FR-negative HaCaT cells. Cellular uptake behavior was visualized by confocal laser scanning microscopy (CLSM). Internalization was time-dependent. Fol-Pep1 and Pep-1 cytotoxicities were negligible up to 25 渭M in FR-positive and FR-negative cells. Empty cF-P-L and dF/P-L were nontoxic at the concentration used. The optimized dF<sub>3sub>/P<sub>2sub>(450/90) system carrying 450 PEG<sub>3400sub>-linked folate and 90 PEG<sub>2000sub>-linked Pep1 molecules could be a good candidate for FR-specific intracellular drug delivery.