LyP-1 modification to enhance delivery of artemisinin or fluorescent probe loaded polymeric micelles to highly metastatic tumor and its lymphatics

Mol Pharm. 2012 Sep 4;9(9):2646-57. doi: 10.1021/mp3002107. Epub 2012 Aug 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Apoptosis / drug effects
  • Artemisinins / administration & dosage*
  • Artemisinins / chemistry*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Carriers / administration & dosage
  • Drug Carriers / chemistry
  • Drug Delivery Systems / methods
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Female
  • Fluorescent Dyes / administration & dosage
  • Fluorescent Dyes / chemistry*
  • Humans
  • Kinetics
  • Lymphatic System / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles*
  • Peptides, Cyclic / metabolism*
  • Polyesters / chemistry
  • Polyethylene Glycols / chemistry
  • Polymers / administration & dosage
  • Polymers / chemistry

Substances

  • Antineoplastic Agents
  • Artemisinins
  • Drug Carriers
  • Fluorescent Dyes
  • LyP-1 peptide
  • Micelles
  • Peptides, Cyclic
  • Polyesters
  • Polymers
  • polycaprolactone
  • Polyethylene Glycols
  • artemisinin