LyP-1 Modification To Enhance Delivery of Artemisinin or Fluorescent Probe Loaded Polymeric Micelles to Highly Metastatic Tumor and Its Lymphatics

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Molecular Pharmaceutics (Impact Factor: 4.38). 08/2012; 9(9):2646-57. DOI: 10.1021/mp3002107
Source: PubMed


Metastatic cancers are prone to form metastasis at a distance and acquire drug resistance, which are very common clinically and major obstacles to successful chemotherapy. Besides the tumor itself, the lymphatic system is increasingly emerging as a new target for anticancer therapy because it is an important route of tumor metastasis. To specifically deliver drug to both highly metastatic tumor and its lymphatics, tumor- and tumor lymphatics-homing peptide (LyP-1) conjugated PEG-PCL micelles (LyP-1-PM) were first constructed. Artemisinin (ART), a natural product with potential anticancer and antilymphangiogenesis effects, was chosen as the model drug and associated into the micelles. Both PM and LyP-1-PM had similar physiochemical properties, about 30 nm in size with uniform distribution. Highly metastatic breast cancer MDA-MB-435S cells and lymphatic endothelial cells (LEC) were applied as cell models. Flow cytometry and confocal microscopy studies showed that LyP-1-PM exhibited its specificity to both cell lines evidenced by its higher cellular uptake than PM. LyP-1-PM-ART demonstrated higher inhibition effect than PM-ART against these two cell lines in cell apoptosis, cell cycle and cytotoxicity tests. Near-infrared imaging showed that LyP-1-PM was distributed more in orthotopic MDA-MB-435S tumor than PM. Further study by colocalization indicated that PM accumulated near blood vessels, while LyP-1-PM further homed to tumor lymphatic vessels. LyP-1-PM achieved higher antitumor efficacy than other ART formulations in vivo with low toxicity. Both in vitro and in vivo studies here proved that LyP-1 modification enhanced the specific delivery of ART or fluorescent probe loaded polymeric micelles to MDA-MB-435S and LEC. Therefore, LyP-1-PM might be promising in terms of specific delivery of therapeutic or imaging agents to both highly metastatic breast tumor and its lymphatics.

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    • "Thus, these cells are prone to the intracellular production of reactive oxygen. The anticancer properties of ART have been extensively investigated and characterized in various experimental settings, including oxidative damage, apoptotic induction, cell cycle arrest, angiogenesis inhibition, aborted lymphatic metastasis and enhanced radiosensitivity (8–13). Dihydroartemisinin (DHA) is the main active metabolite of ART and its antimalarial and antitumor activities are stronger than those of the other ART derivatives. "
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