Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery

Abstract

One of the main goals of nanomedicine is to develop a nanocarrier that can selectively deliver anticancer drugs to the targeted tumors. Extensive efforts have resulted in several tumor-targeted nanocarriers, some of which are approved for clinical use. Most nanocarriers achieve tumor-selective accumulation through the enhanced permeability and retention effect. Targeting molecules such as antibodies, peptides, ligands, or nucleic acids attached to the nanocarriers further enhance their recognition and internalization by the target tissues. While both the stealth and targeting features are important for effective and selective drug delivery to the tumors, achieving both features simultaneously is often found to be difficult. Some of the recent targeting strategies have the potential to overcome this challenge. These strategies utilize the unique extracellular environment of tumors to change the long-circulating nanocarriers to release the drug or interact with cells in a tumor-specific manner. This review discusses the new targeting strategies with recent examples, which utilize the environmental stimuli to activate the nanocarriers. Traditional strategies for tumor-targeted nanocarriers are briefly discussed with an emphasis on their achievements and challenges.

Figure 1

Schematic representation of nanocarriers that passively or actively target tumors. Both types of nanocarriers reach tumors selectively through the leaky vasculature surrounding the tumors. Upon arrival at tumor sites, nanocarriers with targeting molecules can bind to the target tumor cells or enter the cells via specific receptor (cell) – ligand (carrier) interactions, whereas stealth nanocarriers are less efficient in interacting with tumor cells.

Figure 2

Schematic representation of an “extracellularly activated nanocarrier.” The nanocarrier maintains the stealth function during circulation (passive targeting). Upon arrival at the tumor sites, the nanocarriers transform to release the drug or interact with cells in a target-specific manner (active targeting). Such transformation can be triggered by the unique tumoral extracellular environment such as slightly acidic pH or a high level of proteinases.