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Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Key Points

  • Nanoparticulate pharmaceutical drug delivery systems (NDDSs) are used in research and clinical settings to overcome several issues associated with traditional drugs, such as poor aqueous solubility, low bioavailability and nonspecific distribution in the body, and to enhance drug efficiency.

  • Multifunctional NDDSs are able to simultaneously bear a sufficient load of a drug, have increased circulation times and target the drug to the intended site of action. Moreover, they can respond to various stimuli that are characteristic of the pathological site and can even be supplemented with a contrast moiety to enable monitoring of their biodistribution, target accumulation or the efficacy of the therapy.

  • One of the most common properties of NDDSs is the combination of prolonged circulation times with targetabilty. Active targeting of NDDSs can be achieved by surface modification of the NDDS with targeting ligands.

  • Diseases that could benefit from NDDS-based therapy include cancer, cardiovascular diseases and infectious diseases.

  • NDDSs that respond to different types of stimuli are an important and continuously growing area of research. This responsiveness can be used to control the properties and behaviour of NDDSs. The stimuli can be internal and intrinsic for the target site (such as changes in pH, temperature, redox condition or the activity of certain enzymes) or ones that are external and artificially applied (such as a magnetic field, ultrasound and various types of irradiation).

  • After reaching the target, NDDSs may still need to cross the barrier of the cell membrane to deliver their drug load into the cell cytoplasm or specific organelles inside the cell; strategies to facilitate this process have been developed or are under investigation.

  • Multifunctional NDDSs have been constructed for multimodal imaging, which could overcome several problems associated with individual imaging modalities, such as insufficient sensitivity or resolution.

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.

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Figure 1: Schematic of a drug-loaded, multifunctional, stimuli-sensitive NDDS.
Figure 2: Multifunctional and stimuli-sensitive NDDSs in cardiovascular pathologies and infectious diseases.
Figure 3: Penetration of NDDSs into pathological tissue and interaction with target cells.
Figure 4: Methods for targeted drug release.

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Acknowledgements

The author acknowledges US National Institutes of Health grant U54CA151881 and tremendous help by T. Levchenko.

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Glossary

Enhanced permeability and retention (EPR) effect

The property through which macromolecules (such as nanoparticles) accumulate in areas of inflammation including tumours, owing to the increased vascular permeability or abnormal blood vessel architecture.

Passive targeting

The mechanism through which nanoparticulate pharmaceutical drug delivery systems tend to accumulate in tumours, probably through the enhanced permeability and retention effect.

Quantum dots

Nanometre-scale particles of semiconductor materials that have quantum mechanical properties.

Active targeting

The mechanism through which specific moieties attached to nanoparticulate pharmaceutical drug delivery systems force them to interact with a specific type of cell or tissue.

HIV TAT peptide

An amino acid sequence within the HIV transactivator of transcription (TAT) protein. This peptide promotes cell entry as it is a key part of a protein transduction domain.

Theranostics

The simultaneous use of nanoparticulate pharmaceutical drug delivery systems for therapeutic as well as diagnostic and/or imaging purposes.

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Torchilin, V. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13, 813–827 (2014). https://doi.org/10.1038/nrd4333

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