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Amphiphilic block copolymers of poly(ethylene oxide) and poly(propylene oxide) called Pluronic or poloxamer are commercially available pharmaceutical excipients. They recently attracted considerable attention in gene delivery applications. First, they were shown to increase the transfection with adenovirus and lentivirus vectors. Second, they were shown to increase expression of genes delivered into cells using non-viral vectors. Third, the conjugates of Pluronic with polycations, were used as DNA-condensing agents to form polyplexes. Finally, it was demonstrated that they can increase regional expression of the naked DNA after its injection in the skeletal and cardiac muscles or tumor. Therefore, there is substantial evidence that Pluronic block copolymers can improve gene expression with different delivery routes and different types of vectors, including naked DNA. These results and possible mechanisms of Pluronic effects are discussed. At least in some cases, Pluronic can act as biological adjuvants by activating selected signaling pathways, such as NF-κB, and upregulating the transcription of the genes. [ABSTRACT FROM AUTHOR]

Pluronic® block copolymers are known to sensitize multidrug resistant (MDR) tumors with respect to various anticancer agents, particularly, anthracycline antibiotics. After completion of the Phase I clinical trial, the formulation containing doxorubicin and Pluronic®, SP1049C, is undergoing Phase II clinical trials. Studies of the mechanism of the sensitization effect of Pluronic® suggested an essential role of ATP depletion in MDR tumors by the block copolymer. The ATP depletion phenomenon was further examined using a panel of cells with varying levels of expression of P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs). Cell responses were characterized in terms of EC50, a concentration of Pluronic® P85 resulting in a 50% decrease in ATP intracellular levels. These studies suggested that the cells displaying high responses in ATP depletion with EC50<0.01% were strongly sensitized by the block copolymer resulting in drastic increases of doxorubicin cytotoxic activity (over 100-fold). In contrast, the less responsive cells with EC50>ca. 0.02% were practically not sensitized by the block copolymer. The responses of the cells to P85 in ATP depletion studies correlated with the levels of expression of the drug efflux transport proteins, primarily Pgp. This provided initial evidence that Pgp may be useful as a gene expression marker for predicting potential responses to doxorubicin/Pluronic® formulation in chemotherapy of cancer. [Copyright &y& Elsevier]

Pluronic® block copolymers have been used extensively in a variety of pharmaceutical formulations including delivery of low molecular mass drugs and polypeptides. This review describes novel applications of Pluronic® block copolymers in the treatment of drug-resistant tumors. It has been discovered that Pluronic® block copolymers interact with multidrug-resistant cancer (MDR) tumors resulting in drastic sensitization of these tumors with respect to various anticancer agents, particularly, anthracycline antibiotics. Furthermore, Pluronic® affects several distinct drug resistance mechanisms including inhibition of drug efflux transporters, abolishing drug sequestration in acidic vesicles as well as inhibiting the glutathione/glutathione S-transferase detoxification system. All these mechanisms of drug resistance are energy-dependent and therefore ATP depletion induced by Pluronic® block copolymers in MDR cells is considered as one potential reason for chemosensitization of these cells. Following validation using in vitro and in vivo models, a formulation containing doxorubicin and Pluronic® mixture (L61 and F127), SP1049C, has been evaluated in phase I clinical trials. Further mechanistic studies and clinical evaluations of these systems are in progress. [Copyright &y& Elsevier]

Pluronic® block copolymers are found to be an efficient drug delivery system with multiple effects. The incorporation of drugs into the core of the micelles formed by Pluronic® results in increased solubility, metabolic stability and circulation time for the drug. The interactions of the Pluronic® unimers with multidrug-resistant cancer cells result in sensitization of these cells with respect to various anticancer agents. Furthermore, the single molecular chains of copolymer, unimers, inhibit drug efflux transporters in both the blood–brain barrier and in the small intestine, which provides for the enhanced transport of select drugs to the brain and increases oral bioavailability. These and other applications of Pluronic® block copolymers in various drug delivery and gene delivery systems are considered. [Copyright &y& Elsevier]

Pluronic® block copolymers are recognized pharmaceutical excipients listed in the US and British Pharmacopoeia. They have been used extensively in a variety of pharmaceutical formulations including delivery of low molecular mass drugs and polypeptides. This review describes novel applications of Pluronic® block copolymers in gene therapy. In particular, these molecules can modify the biological response during gene therapy in the skeletal muscle, resulting in an enhancement of the transgene expression as well as an enhancement of the therapeutic effect of the transgene. Furthermore, Pluronic® block copolymers are versatile molecules that can be used as structural elements of the polycation-based gene delivery systems (polyplexes). Based on these studies, the use of block copolymers in gene delivery is a promising area of research, in which new and important developments are expected. [Copyright &y& Elsevier]

An abstract of the article "Promoter-Dependence of Plasmid- Pluronics Targeted alpha-Galactosidase A Expression in Skeletal Muscle of Fabry Mice," by Matthieu D. Lavigne, Marita Pohlschmidt, Javier F. Novo, Valery Alakhov, and Dariusz C. Gorecki is presented.

Polymer therapeutics has emerged as a new clinical option for the treatment of human diseases. However, little is known about pharmacogenetic responses to drugs formulated with polymers. In this study, we demonstrate that a formulation containing the block copolymer Pluronic P85 and antineoplastic drug doxorubicin (Dox) prevents the development of multidrug resistance in the human breast carcinoma cell line, MCF7. Specifically, MCF7 cells cultured in the presence of Pluronic were unable to stably grow in concentrations of Dox that exceeded 10 ng of Dox/mL of culture medium. In sharp contrast, MCF7 cells cultured in the absence of the block copolymer resulted in the selection and stable growth of cells that tolerated a 1000 times higher concentration of the drug (10 000 ng of Dox/mL of culture medium). Detailed characterization of the isolated sublines demonstrated that those cells selected in the polymer-drug formulation did not show amplification of the MDR1 gene, likely resulting in their high sensitivity to the drug. Conversely, cells selected with Dox alone showed an elevated level in the expression of the MDR1 gene along with a corresponding increase in the expression level of the drug efflux transporter, Pgp, and likely contributing to the high resistance of the cells to Dox. Global analysis of the expression profiles of 20K genes by DNA microarray revealed that the use of Pluronic in combination with Dox drastically changed the direction and magnitude of the genetic response of the tumor cells to Dox and may potentially enhance therapeutic outcomes. Overall, this study reinforces the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics.

A facile, one-step synthesis of cationic block copolymers of poly(2-N-(dimethylaminoethyl) methacrylate) (pDMAEMA) and copolymers of poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO) has been developed. The PEO-PPO-PEO-pDMAEMA (L92-pDMAEMA) and PEO-pDMAEMA copolymers were obtained via free radical polymerization of DMAEMA initiated by polyether radicals generated by cerium(IV). Over 95% of the copolymer fraction was of molecular mass ranging from 6.9 to 7.1 kDa in size, indicating the prevalence of the polyether-monoradical initiation mechanism. The L92-pDMAEMA copolymers possess parent surfactant-like surface activity. In contrast, the PEO-pDMAEMA copolymers lack significant surface activity. Both copolymers can complex with DNA. Hydrodynamic radii of the complexes of the L92-pDMAEMA and PEO-pDMAEMA with plasmid DNA ranged in size from 60 to 400 nm, depending on the copolymer/DNA ratio. Addition of Pluronic P123 to the L92-pDMAEMA complexes with DNA masked charges and decreased the tendency of the complex to aggregate, even at stoichiometric polycation/DNA ratios. The transfection efficiency of the L92-pDMAEMA copolymer was by far greater than that of the PEO-pDMAEMA copolymer. An extra added Pluronic P123 further increased the transfecton efficacy of L92-pDMAEMA, but did not affect that of PEO-pDMAEMA.