Nanoplatform Assembled from a CD44-Targeted Prodrug and Smart Liposomes for Dual Targeting of Tumor Microenvironment and Cancer Cells

ACS Nano. 2018 Feb 27;12(2):1519-1536. doi: 10.1021/acsnano.7b08051. Epub 2018 Jan 24.

Abstract

The tumor microenvironment (TME) plays a critical role in tumor initiation, progression, invasion, and metastasis. Therefore, a therapy that combines chemotherapeutic drugs with a TME modulator could be a promising route for cancer treatment. This paper reports a nanoplatform self-assembled from a hyaluronic acid (HA)-paclitaxel (PTX) (HA-PTX) prodrug and marimastat (MATT)-loaded thermosensitive liposomes (LTSLs) (MATT-LTSLs) for the dual targeting of the TME and cancer cells. Interestingly, the prodrug HA-PTX can self-assemble on both positively and negatively charged liposomes, forming hybrid nanoparticles (HNPs, 100 nm). Triggered by mild hyperthermia, HA-PTX/MATT-LTSLs HNPs rapidly release their payloads into the extracellular environment, and the released HA-PTX quickly enters 4T1 cells through a CD44-HA affinity. The HNPs possess promoted tumor accumulation (1.6-fold), exhibit deep tumor penetration, and significantly inhibit the tumor growth (10-fold), metastasis (100%), and angiogenesis (10-fold). Importantly, by targeting the TME and maintaining its integrity via inhibiting the expression and activity of matrix metalloproteinases (>5-fold), blocking the fibroblast activation by downregulating the TGF-β1 expression (5-fold) and suppressing the degradation of extracellular matrix, the HNPs allow for significant metastasis inhibition. Overall, these findings indicate that a prodrug of an HA-hydrophobic-active compound and liposomes can be self-assembled into a smart nanoplatform for the dual targeting of the TME and tumor cells and efficient combined treatment; additionally, the co-delivery of MATT and HA-PTX with the HNPs is a promising approach for the treatment of metastatic cancer. This study creates opportunities for fabricating multifunctional nanodevices and offers an efficient strategy for disease therapy.

Keywords: extracellular matrix; matrix metalloproteinases; metastatic breast cancer; prodrug; thermosensitive liposomes; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Delayed-Action Preparations / chemistry
  • Drug Delivery Systems* / methods
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / administration & dosage*
  • Hyaluronic Acid / pharmacokinetics
  • Hyaluronic Acid / pharmacology
  • Hydroxamic Acids / administration & dosage*
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology
  • Liposomes / chemistry
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology
  • Prodrugs / administration & dosage*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • Delayed-Action Preparations
  • Enzyme Inhibitors
  • Hyaluronan Receptors
  • Hydroxamic Acids
  • Liposomes
  • Prodrugs
  • Hyaluronic Acid
  • marimastat
  • Paclitaxel