Stimulus-responsive macromolecules and nanoparticles for cancer drug delivery

Abstract

Nanoparticles and macromolecular carriers have been widely used to increase the efficacy of chemotherapeutics, largely through passive accumulation provided by the enhanced permeability and retention effect. Stimulus-responsive peptide and polymer vehicles can further enhance the efficacy of antitumor therapeutics compared with the administration of free drug by three mechanisms: increasing the overall accumulation within solid tumors; providing a homogeneous spatial distribution in tumor tissues; and increasing the intracellular localization of anticancer therapeutics. This article highlights recent developments in 'smart' - stimulus-responsive - peptide, polymer and lipid drug carriers designed to enhance the localization and efficacy of therapeutic payloads as compared with free drug.

Figure 1. Macromolecule and nanoparticle drug carriers exhibit improved tumor accumulation as compared with low-molecular weight drugs owing to the enhanced permeability and retention effect

Stimulus-responsive drug carriers can further enhance accumulation of the drug, for instance by temperature-triggered coacervation of thermally responsive carriers in heated tumor tissue. Mild hyperthermia of tumors following systemic administration of temperature-responsive biopolymers leads to aggregation of drug vehicles at the vascular wall. When external heating of the tumor is turned off, the aggregated drug carriers redissolve in the tumor vasculature and are driven into the extravascular tumor space owing to the increased local concentration achieved by their aggregation within the tumor vasculature. EPR: Enhanced permeability and retention.

Figure 2. Improved intratumoral distribution can be achieved with release of small-molecular weight drugs in response to tumor-specific stimuli

Attachment of a drug to carrier proteins (A) or polymers (B) through protease-cleavable linkers allows drug release in the presence of overexpressed matrix metalloproteinases in the tumor tissue. Disassembly of drug-loaded micelles in response to low pH (C) improves the diffusion of drug into acidic tumor tissues.

Figure 3. Targeted cellular uptake can be achieved with stimulus-responsive drug carriers

Intrinsic stimuli provide triggers to induce cellular uptake such as cleavage of stealth polymers by tumor proteases (A) and conformational changes in membrane-penetrating peptides in response to the low pH of tumor tissue (B). Extrinsic triggers, such as heat, can be used to trigger multivalent ligand display (C), enhancing the intracellular delivery of anticancer drug vehicles.