Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Abstract

The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases.

Figure 1. Schematic of a drug-loaded, multifunctional, stimuli-sensitive NDDS

Drugs (Drug A and Drug B) can be loaded into a pharmaceutical nanocarrier, such as a liposome or polymeric micelle. Depending on the purpose of the nanoparticulate pharmaceutical drug delivery system (NDDS), various agents can be added to the nanoparticle to target the NDDS to a particular tissue, to increase cell penetration, to enable imaging or to release the drugs in response to a given stimulus. PEG, poly(ethylene glycol).

Figure 2. Multifunctional and stimuli-sensitive NDDSs in cardiovascular pathologies and infectious diseases

a | Nanoparticulate pharmaceutical drug delivery systems (NDDSs) can be engineered to target activated macrophages in atherosclerotic plaques or proteins present in a clot. These nanoparticles can thereby reduce plaque size through these two distinct mechanisms. b | NDDSs can be used to deliver metals to bacteria, where they can generate reactive oxygen species (ROS) to induce membrane blebbing and DNA damage. Antibiotics can also be delivered intracellularly using NDDSs.

Figure 3. Penetration of NDDSs into pathological tissue and interaction with target cells

Moieties attached to nanoparticulate pharmaceutical drug delivery systems (NDDSs) can enhance their penetration into the target tissue or cell. Externally applied stimuli (such as heat) or intrinsic stimuli (such as a change in pH in the target tissue) can cause the NDDS to release its cargo in the vicinity of the target tissue (such as a tumour). Intracellular proteins specific to the target tissue can be used to ensure cargo release in the correct cell type. EPR, enhanced permeability and retention.

Figure 4. Methods for targeted drug release

Various external stimuli can be applied to facilitate intracellular delivery (part a), and various local stimuli, such as enzymes present in the tumour environment, can be used to eliminate the protective poly(ethylene glycol) (PEG) layer from a nanoparticulate pharmaceutical drug delivery system (NDDS) to facilitate its interaction with target cells (part b). MRI, magnetic resonance imaging.