4.7 Article

Ratiometric co-encapsulation and co-delivery of doxorubicin and paclitaxel by tumor-targeted lipodisks for combination therapy of breast cancer

Journal

INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 560, Issue -, Pages 191-204

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2019.02.009

Keywords

Co-loaded lipodisk; Tumor-targeted ratiometric drug delivery; Combination therapy; Doxorubicin; Paclitaxel; Synergistic anticancer effect; Drug resistance

Funding

  1. National Natural Science Foundation of China [81402880, 81602656, 51703086]
  2. Natural Science Foundation of Jiangsu Province for Youth [BK20160496, BK20160546, BK20170533]
  3. Natural Science Foundation of Jiangsu Province [BK20181445]
  4. Scientific Research Foundation of Jiangsu University [14JDG163, 16JDG030]

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Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro, combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) in-corporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained coloaded lipodisks were approximately 30 nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro, as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Co-loaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors, which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues. Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo, potentially enhancing the clinical outcome of synergistic therapy.

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