Polymer genomics: shifting the gene and drug delivery paradigms

doi:10.1016/j.jconrel.2004.07.009

Journal of Controlled Release

Volume 101, Issues 1–3, 3 January 2005, Pages 259-271

https://doi.org/10.1016/j.jconrel.2004.07.009 Get rights and content

Abstract

Pluronic, the A–B–A amphiphilic block copolymers of poly(ethylene oxide) and poly(propylene oxide), can up-regulate the expression of selected genes in cells and alter genetic responses to antineoplastic agents in cancer. Two key new findings are discussed in relation to current drug and gene delivery strategies. First, these block copolymers alone and in combination with a polycation, polyethyleneimine, can up-regulate the expression of reporter genes in stably transfected cells. This underscores the ability of selected synthetic polymers to enhance transgene expression through a mechanism that augments improved DNA delivery into a cell. Second, although, when used alone, Pluronic is “genetically benign,” when combined with an antineoplastic agent, doxorubicin, it drastically alters pharmacogenomic responses to this agent and prevents the development of multidrug resistance in breast cancer cells. Collectively, these studies propose the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics to maximize the clinical outcomes and understand the pharmacological and toxicological effects of polymer-based drugs and delivery systems.

Introduction

This work discusses the effects of synthetic polymers on pharmacogenomic responses to chemotherapeutic agents and the expression of transgenes delivered into cells. We called this new and relatively unexplored field “polymer genomics.” Polymer-based drug and gene delivery systems have emerged from the laboratory bench in the 1990s as a promising therapeutic strategy for the treatment of devastating human diseases [1], [2], [3], [4], [5], [6], [7]. A number of such polymer therapeutics are presently on the market or undergoing clinical evaluations to treat cancer and other diseases. The polymers used in these formulations are usually considered biologically inert excipients that protect biological agents from degradation, prolong exposure of biological agents to tissues, and enhance transport of biological agents into cells. However, such view is undergoing major revision due to growing evidence that selected synthetic polymers, when combined with biological agents (DNA, low-molecular-mass drugs, or antigens), can alter genetically controlled cellular responses to these agents. Few studies noted the ability of polymer therapeutics to alter genetic response in cells [8], [9], [10]. One class of such polymer agents that has attracted attention in drug and gene delivery is Pluronic, the A–B–A triblock copolymer of poly(ethylene oxide) and poly(propylene oxide) [2]. Pluronic block copolymers were shown to sensitize multidrug-resistant (MDR) cancer cells with respect to antineoplastic agents, resulting in improved therapeutic outcomes for MDR tumors [11], [12], [13], [14]. Furthermore, these block copolymers enhance significantly the expression of transgenes delivered in cells with the naked DNA [15], [16], [17], [18], [19], [20], [21], DNA polycation complexes [22], [23], [24], [25], [26], and viruses [27], [28], [29], [30], [31]. This paper provides an overview of the studies demonstrating that Pluronic block copolymers up-regulate the expression of selected genes in the cells. When combined with an antineoplastic agent, doxorubicin, the block copolymer drastically changes the magnitude and direction of the pharmacogenomic responses to this agent.

Section snippets

Pluronic block copolymers as pharmaceutical excipients

Pluronic block copolymers consist of ethylene oxide (EO) and propylene oxide (PO) segments arranged in a basic A–B–A structure: EO_a–PO_b–EO_a (Fig. 1). This arrangement results in an amphiphilic molecule, in which altering the number of EO and PO units can vary the size, hydrophilicity, and lipophilicity of the molecule. Pluronic block copolymers are listed in the US and British Pharmacopoeia under the name “poloxamers,” and are widely used in a variety of pharmaceutical applications in the

Effects of Pluronic block copolymers on gene expression

Cationic lipids and polycations have been used extensively for the design of nonviral gene delivery systems. These studies go back to the end of 1980s and early 1990s when work by Felgner et al. [50], Behr et al. [51], Wu and Wu [52], Kabanov et al. [53], Wagner et al. [54], Zhou et al. [55], and Haensler and Szoka [56] discovered that mixing a plasmid DNA with cationic lipids or polycations resulted in the formation of polymer complexes that efficiently transfected cells. Numerous cationic

Pharmacogenomic effects of Pluronic block copolymers in MDR cancers

Some of the early studies using Pluronic block copolymers focused on the use of polymeric micelles as nanocontainers for targeted delivery of hydrophobic drugs [75], [76], [77]. Yet, it soon became clear that Pluronic molecules themselves display unique properties that have important implications for the delivery of drugs into cells [2]. One notable example is the effects of Pluronic in MDR cancer cells resulting in chemosensitization of these cells to antineoplastic agents [11], [12], [13],

Conclusion

Pluronic block copolymers, when combined with biologically active agents (e.g., genes under selected promoters or low-molecular-mass antineoplastic agent), can alter specific genetically controlled responses to these agents. We posit that Pluronic block copolymers act as biological response modifiers rather than inert excipients to alter the genetic responses. The pharmaceutical industry and heath regulatory authorities have established knowledge and refer to GRAS (“generally regarded as safe”)

Acknowledgements

This work was supported by the US National Institutes of Health grant CA89225, US National Research Foundation grant BES-9907281, and the Nebraska Research Initiative Gene Therapy Program. The assistance of the University of Nebraska Bioinformatics Shared Resource (Dr. S. Sherman) in the analysis of gene expression profiles is acknowledged.

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^☆: The paper was presented at the 8th European Symposium on Controlled Drug Delivery, Noordwijk Aan Zee, The Netherlands, April 7–9, 2004.

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Polymer genomics: shifting the gene and drug delivery paradigms☆

Abstract

Introduction

Section snippets

Pluronic block copolymers as pharmaceutical excipients

Effects of Pluronic block copolymers on gene expression

Pharmacogenomic effects of Pluronic block copolymers in MDR cancers

Conclusion

Acknowledgements

J. Control. Release

Adv. Drug Deliv. Rev.

Molec. Ther.

FEBS Lett.

Cancer Lett.

J. Mol. Cell. Cardiol.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

J. Control. Release

Adv. Drug Deliv. Rev.

J. Control. Release

J. Control. Release

J. Biol. Chem.

Biochim. Biophys. Acta

Pharm. Sci. Technol. Today

Adv. Drug Deliv. Rev.

J. Control. Release

Adv. Drug Deliv. Rev.

J. Biol. Chem.

J. Control. Release

FEBS Lett.

J. Control. Release

Adv. Drug Deliv. Rev.

J. Control. Release

Arch. Biochem. Biophys.

Drug delivery and targeting

Nature

Pluronic block copolymers in drug delivery: from micellar nanocontainers to biological response modifiers

Crit. Rev. Ther. Drug Carr. Syst.

Nonviral gene delivery: techniques and implications for molecular medicine

Expert Rev. Mol. Med.

Polymeric micelle drug carrier systems: PEG-PAsp(Dox) and second generation of micellar drugs

Adv. Exp. Med. Biol.

The dawning era of polymer therapeutics

Nat. Rev., Drug Discov.

Micellar nanocontainers distribute to defined cytoplasmic organelles

Science

Materials science. Enhancing drug function

Science

Differential gene expression profile between PC-14 cells treated with free cisplatin and cisplatin-incorporated polymeric micelles

Bioconjug. Chem.

Toxicogenomics of non-viral vectors for gene therapy: a microarray study of lipofectin- and oligofectamine-induced gene expression changes in human epithelial cells

J. Drug Target.

Hypersensitization of multidrug-resistant human ovarian carcinoma cells by pluronic P85 block copolymer

Bioconjug. Chem.

Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells

Cancer Res.

Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: selective energy depletion

Br. J. Cancer

A combination of poloxamers increases gene expression of plasmid DNA in skeletal muscle

Gene Ther.

In vivo gene delivery into ocular tissues by eye drops of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO) polymeric micelles

Gene Ther.