Alexander V. Kabanov

Pluronic® block copolymers as novel polymer therapeutics for drug and gene delivery

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.

Pluronic Block Copolymers: Evolution of Drug Delivery Concept from Inert Nanocarriers to Biological Response Modifiers

Polymer nanomaterials have sparked a considerable interest as vehicles used for diagnostic and therapeutic agents; research in nanomedicine has not only become a frontier movement but is also a revolutionizing drug delivery field. A common approach for building a drug delivery system is to incorporate the drug within the nanocarrier that results in increased solubility, metabolic stability, and improved circulation time. With this foundation, nanoparticles with stealth properties that can circumvent RES and other clearance and defense mechanisms are the most promising. However, recent developments indicate that select polymer nanomaterials can implement more than only inert carrier functions by being biological response modifiers. One representative of such materials is Pluronic block copolymers that cause various functional alterations in cells. The key attribute for the biological activity of Pluronics is their ability to incorporate into membranes followed by subsequent translocation into the cells and affecting various cellular functions, such as mitochondrial respiration, ATP synthesis, activity of drug efflux transporters, apoptotic signal transduction, and gene expression. As a result, Pluronics cause drastic sensitization of MDR tumors to various anticancer agents, enhance drug transport across the blood brain and intestinal barriers, and causes transcriptional activation of gene expression both in vitro and in vivo. Collectively, these studies suggest that Pluronics have a broad spectrum of biological response modifying activities which make it one of the most potent drug targeting systems available, resulting in a remarkable impact on the emergent field of nanomedicine.

Nanogels as Pharmaceutical Carriers: Finite Networks of Infinite Capabilities

Nanogels are swollen nanosized networks composed of hydrophilic or amphiphilic polymer chains. They are developed as carriers for the transport of drugs, and can be designed to spontaneously incorporate biologically active molecules through formation of salt bonds, hydrogen bonds, or hydrophobic interactions. Polyelectrolyte nanogels can readily incorporate oppositely charged low-molecular-mass drugs and biomacromolecules such as oligo- and polynucleotides (siRNA, DNA) as well as proteins. The guest molecules interact electrostatically with the ionic polymer chains of the gel and become bound within the finite nanogel. Multiple chemical functionalities can be employed in the nanogels to introduce imaging labels and to allow targeted drug delivery. The latter can be achieved, for example, with degradable or cleavable cross-links. Recent studies suggest that nanogels have a very promising future in biomedical applications.

Nanosized cationic hydrogels for drug delivery: Preparation, properties and interactions with cells

A new family of nanoscale materials on the basis of dispersed networks of cross-linked ionic and nonionic hydrophilic polymers is being developed. One example is the nanosized cationic network of cross-linked poly(ethylene oxide) (PEO) and polyethyleneimine (PEI), PEO-cl-PEI nanogel. Interaction of anionic amphiphilic molecules or oligonucleotides with PEO-cl-PEI results in formation of nanocomposite materials in which the hydrophobic regions from polyion-complexes are joined by the hydrophilic PEO chains. Formation of polyion-complexes leads to the collapse of the dispersed gel particles. However, the complexes form stable aqueous dispersions due to the stabilizing effect of the PEO chain. These systems allow for immobilization of negatively charged biologically active compounds such as retinoic acid, indomethacin and oligonucleotides (bound to polycation chains) or hydrophobic molecules (incorporated into nonpolar regions of polyion-surfactant complexes). The nanogel particles carrying biological active compounds have been modified with polypeptide ligands to enhance receptor-mediated delivery. Efficient cellular uptake and intracellular release of oligonucleotides immobilized in PEO-cl-PEI nanogel have been demonstrated. Antisense activity of an oligonucleotide in a cell model was elevated as a result of formulation of oligonucleotide with the nanogel. This delivery system has a potential of enhancing oral and brain bioavailability of oligonucleotides as demonstrated using polarized epithelial and brain microvessel endothelial cell monolayers.

Pluronic® block copolymers for overcoming drug resistance in cancer

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.

Evaluation of polyether-polyethyleneimine graft copolymers as gene transfer agents

Cationic copolymers consisting of polycations linked to non-ionic polymers are evaluated as non-viral gene delivery systems. These copolymers are known to produce soluble complexes with DNA, but only a few studies have characterized the transfection activity of these complexes. This work reports the synthesis and characterization of a series of cationic copolymers obtained by grafting the polyethyleneimine (PEI) with non-ionic polyethers, poly (ethylene oxide) (PEO) or Pluronic 123 (P123). The PEO–PEI conjugates differ in the molecular mass of PEI (2 kDa and 25 kDa) and the degree of modification of PEI with PEO. All of these conjugates form complexes upon mixing with plasmids, which are stable in aqueous dispersion for several days. The sizes of the particles formed in these systems vary from 70 to 200 nm depending on the composition of the complex. However, transfection activity of these systems is much lower than that of PEI (25 kDa) or Superfect as assessed in in vitro transfection experiments utilizing a luciferase reporter expression in Cos-7 cells as a model system. In contrast, conjugate of P123 with PEI (2 kDa) mixed with free P123 (9:1(wt)) forms small and stable complexes with DNA (110 nm) that exhibit high transfection activity in vitro. Furthermore, gene expression is observed in spleen, heart, lungs and liver 24 h after i.v. injection of this complex in mice. Compared to 1,2-bis(oleoyloxy)-(trimethylammonio) propane:cholesterol (DOTAP:Chol) and PEI (25 kDa) transfection systems, the P123-PEI system reveals a more uniform distribution of gene expression between these organs, allowing a significant improvement of gene expression in liver.

PLURONIC BLOCK COPOLYMERS: NOVEL FUNCTIONAL MOLECULES FOR GENE THERAPY

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.

Micellar enzymology: its relation to membranology

Micellar enzymology, a new trend in molecular biology, studies catalysis by enzymes entrapped in hydrated reversed micelles composed of surfactants (phospholipids, detergents) in organic solvents. The key research problems of micellar enzymology and its relation to enzyme membranology are discussed.

The neuroleptic activity of haloperidol increases after its solubilization in surfactant micelles: Micelles as microcontainers for drug targeting

It has been suggested to use surfactant micelles as microcontainers for increasing the efficiency of neuroleptic targeting from blood flow into the brain. The neuroleptic action of haloperidol, intraperitoneally injected into mice in micellar solution of non‐ionic block copolymer surfactant (pluronic P‐85) in water, increased several‐fold if compared with that observed for haloperidol aqueous solution. Incorporation of brain‐specific antibodies into haloperidol‐containing micelles resulted in additional drastic increase (more than by 2 orders of magnitude) in the drug effect.

Pluronic® block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier

Drug efflux transporters can influence the absorption, tissue distribution and elimination of many therapeutic agents. Modulation of drug efflux transporter activity is being explored as a means for improving the pharmacokinetic and pharmacodynamic properties of various drugs. In this regard, several polymer formulations have been shown to inhibit drug efflux transporters such as P-glycoprotein (P-gp). The current review will focus on Pluronic block copolymers in particular, the mechanisms involved in the effects of Pluronic on drug efflux transporters, and the optimal polymer compositions required for inhibition of drug efflux transporters. Special emphasis will be placed on the potential applications of Pluronic in enhancing the blood-brain barrier (BBB) penetration of drugs.