Polymer genomics: shifting the gene and drug delivery paradigms☆
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: EOa–POb–EOa (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.
References (83)
- et al.
Preliminary evaluation of caspases-dependent apoptosis signaling pathways of free and HPMA copolymer-bound doxorubicin in human ovarian carcinoma cells
J. Control. Release
(2001) - et al.
Pluronic block copolymers for overcoming drug resistance in cancer
Adv. Drug Deliv. Rev.
(2002) - et al.
Electroporation-facilitated delivery of plasmid DNA in skeletal muscle: plasmid dependence of muscle damage and effect of poloxamer 188
Molec. Ther.
(2001) - et al.
Enhancement of the polycation-mediated DNA uptake and cell transfection with Pluronic P85 block copolymer
FEBS Lett.
(1996) - et al.
Improvement of gene transfer to cervical cancer cell lines using non-viral agents
Cancer Lett.
(2001) - et al.
Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for gene therapy
J. Mol. Cell. Cardiol.
(2003) - et al.
Long circulating microparticulate drug carriers
Adv. Drug Deliv. Rev.
(1995) - et al.
Targeting of colloids to lymph nodes: influence of lymphatic physiology and colloidal characteristics
Adv. Drug Deliv. Rev.
(1995) Block copolymers in pharmaceutics
- et al.
Recent advances in cellular, sub-cellular and molecular targeting
Adv. Drug Deliv. Rev.
(2000)
Understanding drug release from poly(ethylene oxide)–β-poly(propylene oxide)–β-poly(ethylene oxide) gels
J. Control. Release
Block copolymer micelles for drug delivery: design, characterization and biological significance
Adv. Drug Deliv. Rev.
Structure and design of polymeric surfactant-based drug delivery systems
J. Control. Release
Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery
J. Control. Release
Receptor-mediated in vitro gene transformation by a soluble DNA carrier system
J. Biol. Chem.
Lipophilic polylysines mediate efficient DNA transfection in mammalian cells
Biochim. Biophys. Acta
Taking polycation gene delivery systems from in vitro to in vivo
Pharm. Sci. Technol. Today
Design and gene delivery activity of modified polyethylenimines
Adv. Drug Deliv. Rev.
Development of non-viral vectors for systemic gene delivery
J. Control. Release
Block copolymer micelles for delivery of gene and related compounds
Adv. Drug Deliv. Rev.
Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations
J. Biol. Chem.
Protective interactive noncondensing (PINC) polymers for enhanced plasmid distribution and expression in rat skeletal muscle
J. Control. Release
The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles. Micelles as microcontainers for drug targeting
FEBS Lett.
A new class of drug carriers: micelles of poly(oxyethylene)–poly(oxypropylene) block copolymers as microcontainers for drug targeting from blood in brain
J. Control. Release
Pluronic® block copolymers as modulators of drug efflux transporter activity in the blood–brain barrier
Adv. Drug Deliv. Rev.
An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers
J. Control. Release
Effect of a polymeric surfactant on electron transport in HL-60 cells
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.
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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.