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Polymer–drug conjugate therapeutics: advances, insights and prospects

Abstract

Polymer–drug conjugates have long been a mainstay of the drug delivery field, with several conjugates successfully translated into clinical practice. The conjugation of therapeutic agents to polymeric carriers, such as polyethylene glycol, offers several advantages, including improved drug solubilization, prolonged circulation, reduced immunogenicity, controlled release and enhanced safety. In this Review, we discuss the rational design, physicochemical characteristics and recent advances in the development of different classes of polymer–drug conjugates, including polymer–protein and polymer–small-molecule drug conjugates, dendrimers, polymer nanoparticles and multifunctional systems. Current obstacles hampering the clinical translation of polymer–drug conjugate therapeutics and future prospects are also presented.

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Fig. 1: Classes of polymer–drug conjugates on the market or in clinical development.
Fig. 2: Emerging approaches in polymer–protein conjugate development.
Fig. 3: Architectural diversity of polymer therapeutics.
Fig. 4: Stimuli-responsive functionalities and schematic representation of a multifunctional polymer therapeutic.

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Acknowledgements

This work was supported in part by funding from the National Institutes of Health (R01EB017722, R01CA227433), the National Science Foundation (DGE-1247312 (I.E.), DMR-1507081), the Michael A. Bell Family Distinguished Chair in Healthcare Innovation at Brigham and Women’s Hospital (Y.L.C.) and the Distinguished Professor of Translational Research Chair at Boston University (M.W.G.).

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Correspondence to Yolonda L. Colson or Mark W. Grinstaff.

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M.W.G. and I.E. are co-inventors on a patent application describing a new polymer for drug conjugation (US20170369643A1) owned by Boston University and available for license.

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Glossary

Bioactives

Molecules that elicit a biological response.

Excipient

A non-active substance formulated with an active pharmaceutical ingredient to enhance physicochemical characteristics such as stability and solubility.

Opsonization

The process by which foreign materials are coated with opsonin proteins to enhance their phagocytic uptake and clearance.

Semi-telechelic

A polymer with one reactive end group.

Zwitterionic

An electrically neutral molecule with at least one positive and one negative functional group.

Biodistribution

The distribution of a molecule within the body.

AUC

The area under the plasma drug concentration versus time curve. Larger AUC values are indicative of increased drug exposure.

C max

The maximal concentration of drug achieved after administration.

Therapeutic index

The ratio of the dose needed to elicit a toxic side effect relative to the dose needed to elicit a therapeutic effect. A larger therapeutic index is indicative of a safer drug.

Avidity

The cumulative strength of a binding interaction.

Theranostic

A system that combines therapeutic and imaging modalities for both treatment and diagnosis.

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Ekladious, I., Colson, Y.L. & Grinstaff, M.W. Polymer–drug conjugate therapeutics: advances, insights and prospects. Nat Rev Drug Discov 18, 273–294 (2019). https://doi.org/10.1038/s41573-018-0005-0

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