International Journal of Nanomedicine (Nov 2018)
Fabrication and evaluation of a γ-PGA-based self-assembly transferrin receptor-targeting anticancer drug carrier
Abstract
Li Zhang, Xiaoyu Zhu, Shijia Wu, Yazhou Chen, Shiming Tan, Yingjie Liu, Wenzheng Jiang, Jing Huang School of Life Sciences, East China Normal University, Shanghai 200241, China Background: cis-Dichlorodiamineplatinum (CDDP) was one of the most common used drugs in clinic for cancer treatment. However, CDDP caused a variety of side effects. The abundant carboxyl groups on the surface of poly glutamic acid (PGA) could be modified with various kinds of targeted ligands. PGA delivery system loaded CDDP for cancer therapies possesses potential to overcome the side effects.Materials and methods: In this study, we constructed a safe and efficient anticancer drug delivery system PGA–Asp–maleimide–cisplatin–peptide complex (PAMCP), which was loaded with CDDP and conjugated with the transferrin receptor (TFR)-targeting peptide through a maleimide functional linker. The size of PAMCP was identified by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Fluorescence microscopy and flow cytometry methods were used to detect the cell targeting ability in vitro. The MTT assay was used to detect targeted toxicity in vitro. The in vivo acute toxicity was tested in Kun Ming (KM) mice. The tumor suppression activity and drug distribution was analyzed in nude mice bearing with HeLa tumor cells.Results: The nano-size was 110±28 nm detected with TEM and 89±18 nm detected with DLS, respectively. Fluorescence microscopy and flow cytometry methods indicated that PAMCP possessed excellent cell targeting ability in vitro. The MTT assay suggested that PAMCP was excellent for targeted toxicity. The acute in vivo toxicity study revealed that the body mass index and serum index in the PAMCP-treated group were superior to those in the CDDP-treated group (P<0.001), and no obvious differences were detected on comparing with the PBS- or PGA–Asp–maleimide–P8 (PAMP)-treated groups. PAMCP reduced the toxicity of CDDP, suppressed tumor cell growth, and achieved efficient anti-tumor effects in vivo. After PAMCP treatment, the toxicity of CDDP was reduced and tumor growth was more remarkably inhibited compared with the free CDDP treatment group (P<0.01). Much stronger (5–10 folds) fluorescence intensity in tumor tissue was detected compared with the irrelevant-peptide group for drug distribution analysis detected with the frozen section approach.Conclusion: Our data highlighted that PAMCP reduced the side effects of CDDP and exhibited stronger anti-tumor effects. Therefore, PAMCP presented the potential to be a safe and effective anticancer pharmaceutical formulation for future clinical applications. Keywords: cisplatin, tumor suppression, side effects, targeted drug delivery system
