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  • Review Article
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Polymer conjugates as anticancer nanomedicines

Key Points

  • Water-soluble polymers conjugated to proteins and anticancer drugs are in routine clinical use and clinical development as both single agents and components of combination therapy. This is establishing polymer therapeutics as one of the first classes of anticancer nanomedicine. There is growing optimism about the use of ever more sophisticated polymer-based vectors for cancer therapy.

  • The covalent conjugation of synthetic polymers, particularly poly(ethyleneglycol) (PEG), to protein drugs increases their plasma residence, reduces protein immunogenicity and can increase their therapeutic index. Several PEGylated enzymes (such as L-asparaginase) and cytokines (including interferon-α and granulocyte colony-stimulating factor) have now entered routine clinical use.

  • Polymer conjugation alters the biodistribution of low-molecular-weight drugs, enabling tumour-specific targeting with reduced access to sites of toxicity. More than ten polymer–anti-tumour conjugates have been transferred into clinical development. They have been designed for lysosomotropic delivery following passive tumour targeting by the enhanced permeability and retention effect (EPR effect) or, in one case, for receptor-mediated targeting by the introduction of a cell-specific ligand. Polyglutamic acid–paclitaxel is showing particular promise in phase III trials in women with non-small-cell lung cancer.

  • New strategies are making polymer conjugates active against new molecular targets (for example, anti-angiogenics), and the combination of polymer conjugates with low-molecular-weight drugs (which are routinely used in chemotherapy), radiotherapy or tailor-made prodrugs is showing promise. Moreover, the polymer platform provides an ideal opportunity to deliver a drug combination from a single carrier, and combined endocrine therapy and chemotherapy is showing preclincal potential as a breast cancer therapy.

  • The polymers that have been used clinically so far have a linear polymer architecture. The principles for the design of polymer therapeutics are now being applied to new hyperbranched dendrimers and dendritic polymer architectures. Before clinical evaluation it is essential to establish the safety of new polymers, particularly in respect of general toxicity, immunogenicity and metabolic fate.

Abstract

The transfer of polymer–protein conjugates into routine clinical use, and the clinical development of polymer–anticancer-drug conjugates, both as single agents and as components of combination therapy, is establishing polymer therapeutics as one of the first classes of anticancer nanomedicines. There is growing optimism that ever more sophisticated polymer-based vectors will be a signficant addition to the armoury currently used for cancer therapy.

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Figure 1: Polymer–anticancer drug conjugates.
Figure 2: Current understanding of the mechanism of action of polymer–drug conjugates.

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Acknowledgements

Thanks to H. Ringsdorf, J. Singer and M. Jesus Vicent for critically reading the manuscript and for their suggested improvements. Also thanks to W. Meeson for editorial assistance. With the growing realization that biotechnology and nanotechnology can contibute to improved cancer care, I would like to recognize the contributions of many aquaintances, colleagues, collaborators and friends (you know who you are) who have helped to realize polymer therapeutics, other drug targeting systems and innovative therapeutics (including monoclonal antibodies and anti-angiogenic strategies). Even though there is still much to do, your persistence and never-ending faith (in the face of those who doubted) has laid a solid foundation for the continued development of these approaches into the 21st Century.

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DATABASES

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ALL

brain cancer

breast cancer

liver cancer

lung cancer

melanoma

non-Hodgkin lymphoma

prostate

renal cell carcinoma

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Glossary

Controlled release

Controlled release dosage forms maintain a constant plasma concentration of drug over a prolonged period of time.

Nanomedicine

The newly emerging discipline called 'nanomedicine' describes the application of 'nanotechnology' (usually viewed as 1–1,000 nm) to: the design of systems and devices that can be used to facilitate a better understanding of disease pathophysiology and therefore enable new target identification for therapeutic intervention; nanoimaging at the cellular and patient level; and the design of nanomedicines and nanodiagnostics. Underpinning fields are nano-related materials, nano-related engineering and nano-related toxicology.

Nanopharmaceuticals or nanomedicines

The umbrella term used to describe nano-sized (1–1,000 nm) drugs and drug-delivery systems used as medicines that consist of more than one component.

Liposomes

Lipid-based vesicles used to entrap a drug payload and promote disease-specific targeting.

Nanoparticle

Tiny particles, usually of 20–500 nm dimensions, and formed from natural or synthetic polymers that are used to entrap drugs for improved drug targeting and controlled release.

Therapeutic index

The comparison of the drug dose that produces toxicity to the therapeutic dose.

Topical administration

The application of drugs to the skin.

Parenteral administration

The administration of drugs directly into the body by injection or infusion.

Micelle

A self-assembling colloidal aggregate of amphipathic molecules, in this case polymeric block copolymers, to give a polymeric micelle, which occurs when the concentration reaches the critical micelle concentration.

Dendrimer

A macromolecule that contains symmetrically arranged branches arising from a multifunctional core. Repeated reaction sequences add a precise number of terminal groups at each step or generation.

Neutropaenia

A decrease in circulating neutrophils (white blood cells) in the peripheral blood.

Maximum-tolerated dose

The maximum dose of a drug that can be given to a patient without inducing severe or life-threatening side effects.

Thrombocytopaenia

A decrease in platelets in the peripheral blood.

Dose-limiting toxicity

The particular type of toxicity responsible for the inability to raise a drug dose without the fear of severe or life-threatening side effects.

Endocytosis

The internalization of a cell's plasma membrane to form vesicles that capture macromolecules and particles present in the extracellular fluid and/or bound to membrane-associated receptors. These vesicles then undergo a complex series of fusion events directing the internalized vesicle to an appropriate intracellular compartment.

Polymer–drug loading

The amount of drug carried by a polymer – this value is usually expressed as wt%.

Lysosomotropic

Molecules that are delivered to lysosomes and accumulate there. Applied in this context to polymeric constructs taken into the cell by endocytosis.

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Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 6, 688–701 (2006). https://doi.org/10.1038/nrc1958

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