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  • Review Article
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The dawning era of polymer therapeutics

Key Points

  • Polymer therapeutics are nano-sized medicines. The definition encompasses polymeric drugs (polymeric molecules that are biologically active in their own right); polymer–drug conjugates; polymer–protein conjugates; polymeric micelles to which drug is covalently bound; and polymeric non-viral vectors for gene delivery.

  • An increasing number of biologically active polymers and polymeric sequestrants are entering routine clinical use as macromolecular drugs. Multivalent synthetic polymers are also being developed as improved vaccines and anti-toxin therapeutics.

  • Covalent conjugation of synthetic polymers — particularly polyethyleneglycol (PEG) — to protein drugs increases their plasma residence, reduces protein immunogenicity and can increase therapeutic index. Several PEGylated enzymes (adenosine deaminase, L-asparaginase) and cytokines (including interferon α and G-CSF) have now entered routine clinical use.

  • Polymer conjugation dramatically alters the biodistribution of a low molecular weight drug, affording the opportunity to achieve disease-specific targeting with reduced access to sites of toxicity. Eleven polymer antitumour conjugates have been transferred into clinical development. They have been designed for lysosomotropic delivery following passive tumour targeting by the enhanced permeability and retention (EPR) effect, or, in one case, for receptor-mediated targeting by introduction of a cell-specific ligand.

  • Cationic or bio-responsive polymers that change conformation on exposure to the lower intracellular pH of endosomes and lysosomes are being developed as an alternative to viral vectors, for intracytoplasmic delivery of genes and proteins.

  • Those polymers that have been exploited clinically have a linear polymer architecture. The principles for the design of polymer therapeutics are now being applied to novel hyperbranched polymers, dendrimers and dendritic polymer architectures.

  • Before clinical evaluation, it is essential to establish the safety of novel polymers, particularly with respect to general toxicity, immunogenicity and metabolic fate.

Abstract

As we enter the twenty-first century, research at the interface of polymer chemistry and the biomedical sciences has given rise to the first nano-sized (5–100 nm) polymer-based pharmaceuticals, the 'polymer therapeutics'. Polymer therapeutics include rationally designed macromolecular drugs, polymer–drug and polymer–protein conjugates, polymeric micelles containing covalently bound drug, and polyplexes for DNA delivery. The successful clinical application of polymer–protein conjugates, and promising clinical results arising from trials with polymer–anticancer-drug conjugates, bode well for the future design and development of the ever more sophisticated bio-nanotechnologies that are needed to realize the full potential of the post-genomic age.

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Figure 1: Schematic representation of polymer therapeutics now in, or progressing towards, clinical development.
Figure 2: Novel polymeric architectures now being explored as the polymer therapeutics of the future.
Figure 3: Biological rationale for the design of polymeric anticancer therapeutics (part 1).
Figure 4: Biological rationale for the design of polymeric anticancer therapeutics (part 2).
Figure 5: Examples of polymer–drug conjugates that are being evaluated as anticancer agents.

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Glossary

MICELLES

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 crucial micelle concentration.

POLYPLEX

A polyelectrolyte complex. The term is usually used to describe the complex formed by a polycation and an anionic oligonucleotide or plasmid. The term interpolyelectrolyte complex (IPEC) is also used.

BIOACTIVE

A substance capable of eliciting a measurable biological response.

BIOMIMETIC

A term that describes a structure that is designed to mimic the properties of a natural macromolecule, for example, a synthetic multivalent ligand designed for receptor interaction.

DENDRIMER

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

SUPRAMOLECULAR SYSTEM

Self-assembled objects generated by intermolecular noncovalent interactions. They may be super molecules or polymolecular assemblies.

APOPTOSIS

A mechanism of programmed cell death, which occurs when a cell receives mixed internal signals for growth or when stimulated by an external trigger. Apoptosis can be initiated when a cell is no longer needed, or when a cell becomes a threat to the organism's health.

ANGIOGENESIS

The process by which small new blood vessels are formed by budding from existing vessels in both normal and diseased (for example, tumour) tissue.

HAEMOLYTIC

Materials that cause breakage of the red blood cell membrane, and the release of haemoglobin.

ENDOCYTOSIS

Internalization of the 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 substances to an appropriate intracellular compartment.

LYSOSOMOTROPIC

A term that describes molecules that are delivered to lysosomes and accumulate there. In this context, it is applied to polymeric constructs that are taken into the cell by endocytosis.

GAMMA CAMERA

A device incorporating very sensitive radiation detectors, which produces images of the distribution of radioactivity in the body in patients who have been injected with small amounts of radioactive materials. These images can be used to detect and locate disease (such as cancer) if it is present. The device itself does not emit radiation.

ENDOSOMOTROPIC

A term that describes molecules that are delivered to the endosomal compartment of the cell and accumulate there. In this context, it is applied to polymer constructs that are designed as viral mimetics with the aim of breaching the endosomal membrane, and delivering proteins and oligonucleotides into the cytoplasm of the cell.

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Duncan, R. The dawning era of polymer therapeutics. Nat Rev Drug Discov 2, 347–360 (2003). https://doi.org/10.1038/nrd1088

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