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Biomedical subjects

Alexander V Kabanov

Publications and source records attributed to Alexander V Kabanov.

At least 19 recordsLinked to original sources
PubMed2006

Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis.

Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood-brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.

AIDS Dementia Complex↗
PubMed2006

Polymer genomics: an insight into pharmacology and toxicology of nanomedicines.

Synthetic polymers and nanomaterials display selective phenotypic effects in cells and in the body signal transduction mechanisms involved in inflammation, differentiation, proliferation, and apoptosis. When physically mixed or covalently conjugated with cytotoxic agents, bacterial DNA or antigens, polymers can drastically alter specific genetically controlled responses to these agents. These effects, in part, result from cooperative interactions of polymers and nanomaterials with plasma cell membranes and trafficking of polymers and nanomaterials to intracellular organelles. Cells and whole organism responses to these materials can be phenotype or genotype dependent. In selected cases, polymer agents can bypass limitations to biological responses imposed by the genotype, for example, phenotypic correction of immune response by polyelectrolytes. Overall, these effects are relatively benign as they do not result in cytotoxicity or major toxicities in the body. Collectively, however, these studies support the need for assessing pharmacogenomic effects of polymer materials to maximize clinical outcomes and understand the pharmacological and toxicological effects of polymer formulations of biological agents, i.e. polymer genomics.

Animals↗
PubMed2006

Block ionomer complexes as prospective nanocontainers for drug delivery.

Nanosized environmentally responsive materials are of special interest for various applications, including drug delivery. Block ionomer complexes (BIC) composed of graft-comb copolymers of Pluronic and poly(acrylic acid) (Pluronic-PAA) and a model cationic surfactant, hexadecyltrimethylammonium bromide (HTAB), were synthesized by mixing the polymer and surfactant in aqueous media. According to TEM, the resulting BIC represented spherical particles of nanoscale size (50 to 100 nm). The stability of the BIC in the aqueous dispersion depended on the lengths of the hydrophilic poly(ethylene oxide) and hydrophobic poly(propylene oxide) chains in Pluronic molecules as well as on the surface charge of the resulting complexes. The latter was controlled by changing the ratio of the Pluronic-PAA and HTAB in the BIC and by changing the pH due to reversible ionization of the PAA chains. The acidification of the media below pH 6.0 resulted in the appearance of a strong positive charge on the BIC, which in the intracellular environment can trigger interaction of such BIC with the cell membranes. An efficient solubilization of a model hydrophobic molecule, Sudan III, and a drug, Etoposide, in such BIC was demonstrated with the loading capacities of about 6 to 15% by weight of the dispersed complex. Overall, these BIC wield a promise as environmentally responsive nanocarriers for pharmaceuticals.

Acrylic Resins↗
PubMed2006

Polymer micelles with cross-linked ionic cores for delivery of anticancer drugs.

This work reports the design of polymer micelles with cross-linked ionic cores that display high stability. Block ionomer complexes of poly(ethylene oxide)-b-poly(methacrylic acid) copolymer and divalent metal cations were utilized as micellar templates for the synthesis of the cross-linked micelles. Such micelles represent hydrophilic nanospheres of core-shell morphology. The core comprises a network of the cross-linked polyanions, which is surrounded by the shell of hydrophilic PEO chains. The ionic character of the core provided for pH-dependent swelling/collapse behavior of the nanogels. Cisplatin, a potent chemotherapeutic agent, was incorporated into the ionic core of the micelles with remarkably high efficiency (22% w/w). The drug-loaded micelles were stable in aqueous dispersions exhibiting no aggregation or precipitation for a prolonged period of time. Slow release of platinum complexes was observed in sustained manner from the cisplatin-loaded cross-linked micelles in physiological saline. In vitro studies using human A2780 ovarian carcinoma cells demonstrated that the cross-linked micelles rapidly internalized and delivered cisplatin into cells. These results indicated that polymer micelles with cross-linked ionic cores are promising for further fundamental material studies and practical applications as drug delivery carriers.

Antineoplastic Agents↗
PubMed2006

Nanotools for megaproblems: probing protein misfolding diseases using nanomedicine modus operandi.

Misfolding and self-assembly of proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed protein misfolding diseases. Recent studies highlight increasing recognition of the public health importance of protein misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated proteins. Altogether, the accumulation of abnormal protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic proteins. Formulation of these therapeutic proteins into delivery systems and their in vivo delivery are often complicated by protein association. Thus, protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to misfolding and self-assembly responsible for various protein folding pathologies. This article overviews protein misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders.

Amyloidosis↗
PubMed2006

Template-assisted synthesis of nanogels from Pluronic-modified poly(acrylic acid).

A series of novel polymeric nanogels with core-shell morphology was developed. Block ionomer complexes of comb-graft poly(ethylene oxide)-b-poly(polypropylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) copolymers (Pluronic-PAA) and divalent metal cations were utilized as micellar templates for the synthesis of nanogels with sizes ranging from 100 to 200 nm in diameter. The Pluronic-PAA nanogels were confirmed to possess ionic cross-linked PAA cores and flexible hydrophilic shells from the Pluronic copolymer chains. The ionic character of the core provided for pH-dependent swelling/collapse behavior of the nanogels. These prepared nanogels are expected to be of utility as carriers for charged therapeutic or diagnostic agents.

Acrylates↗
PubMed2005

Polyplex Nanogel formulations for drug delivery of cytotoxic nucleoside analogs.

Hydrophilic nanosized particles consisting of the cross-linked cationic polymer network (Nanogels) are suggested as a drug delivery system for nucleoside analog 5'-triphosphates, an active form of cytotoxic anticancer drugs. Preparation, properties, and cellular effects of several polyplex Nanogel formulations with the 5'-triphosphate of cytotoxic 5-fluoroadenine arabinoside (fludarabine) (FATP) were examined and discussed here. The polyplexes have formed spontaneously by mixing solutions of FATP and Nanogels because of ionic interactions between protonated polyethylenimine (PEI) chains in Nanogel network with polyphosphate groups of the drug. Subsequent compaction of the flexible Nanogel network has resulted in an encapsulation of the FATP/PEI complex in a dense core surrounded by hydrophilic poly(ethylene glycol) (PEG) envelope. This structure has provided a sustained release of the drug, as well as an efficient protection of FATP against enzymatic degradation. The drug loading could reach up to 33% by weight of the drug-Nanogel formulation. In vitro 35% of loaded drug has released from Nanogel formulations during the first 24 h, and a slower additional release was observed during the next 2 days. Nanogels have protected 90% of the encapsulated FATP from enzymatic dephosphorylation during the first 60 min of incubation in vitro. The drug-Nanogel formulation compared to the drug has demonstrated a significantly enhanced cytotoxicity in cultured cancer cells. Cancer cell-targeting molecules, such as folate, could be easily attached to Nanogels and this modification has resulted in a strong 10-fold increase of the carrier's internalization in human breast carcinoma MCF-7 cells. Moreover, transcellular transport of the folate-Nanogel polyplexes was found to be 4 times more effective compared to the drug alone using Caco-2 cell monolayers as an in vitro intestinal model. The data demonstrate that this carrier-based approach to delivery of cytotoxic drugs may enhance tumor specificity and significantly reduce side effects related to systemic toxicity usually observed during cancer chemotherapy.

Breast Neoplasms↗
PubMed2005

Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells.

Pluronic block copolymer P85 (P85) sensitizes multidrug resistant (MDR) cancer cells resulting in the increase of cytotoxic activity of antineoplastic agents. This effect is attributed to the inhibition of the most clinically relevant drug efflux transporter, P-glycoprotein (Pgp), through the combined ATP depletion and inhibition of Pgp ATPase activity. The present study elucidates effects of an anticancer agent, doxorubicin (Dox), formulated with P85 on drug-induced apoptosis in MDR cancer cells. Early and late stages of apoptosis were detected by Annexin V and TUNEL methods, respectively. In parallel experiments, the expression of genes related to apoptosis, BCL2, BCLXL, BAX, P53, APAF1, Caspase 3, and Caspase 9, was determined by RT-PCR. The obtained data suggest that Dox/P85 formulation induces apoptosis in the resistant cancer cells more efficiently than free Dox. The treatment of the cells with Dox alone simultaneously activated a proapoptotic signal and an antiapoptotic cellular defense. Therefore, the apoptosis induction by Dox was substantially limited. In contrast, the treatment of the cells with Dox/P85 formulation significantly enhanced the proapoptotic activity of the drug and prevented the activation of the antiapoptotic cellular defense. This is likely to result in the stronger cytotoxic response of the resistant cells to the Dox/P85 formulation compared to the free drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Polymer micelle with cross-linked ionic core.

This work reports the design of polymer micelles with cross-linked ionic cores that display high stability. Block ionomer complexes were utilized as a micellar template for the synthesis of the cross-linked micelles. Such micelles represent hydrophilic nanospheres of core-shell morphology. The core comprises a network of the cross-linked polyanions, which is surrounded by the shell of hydrophilic PEO chains.

Calcium↗
PubMed2005

Fluorescence anisotropy study of aqueous dispersions of block ionomer complexes.

Block ionomer complexes (BIC) of "dual hydrophilic" block copolymers containing ionic and nonionic blocks and oppositely charged surfactants spontaneously form colloidal particles of ca. 80 nm in diameter stable in aqueous dispersions at every composition of the mixture. Packing and dynamics of aliphatic groups of the surfactant in BIC were examined by using the quenching-resolved fluorescence anisotropy (QRFA) method with 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe. The values of the order parameter and rotational relaxation time in the BIC were higher than those in the surfactant micelles. Incorporation of aliphatic alcohols in the BIC decreased the order parameter and increased the rotational relaxation time. The effects on the order parameter were explained by changes in the surfactant aliphatic group conformation to "fill the gaps" induced by insertion of shorter alcohol molecules. The effects on the relaxation time were attributed to a decrease in repulsion of the surfactant headgroups and expulsion of water from the BIC hydrophobic interior as evidenced by the decrease in micropolarity. The results of this study have implications for potential use of the BIC in pharmaceutics and other fields.

Alcohols↗
PubMed2005

Polymer genomics: shifting the gene and drug delivery paradigms.

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.

Animals↗
PubMed2004

Distribution kinetics of a micelle-forming block copolymer Pluronic P85.

Pluronic block copolymers, micelle-forming polymeric surfactants, are currently being evaluated in chemotherapy clinical trials in combination with doxorubicin to treat multidrug-resistant (MDR) tumors. This study examines the pharmacokinetics and biodistribution of Pluronic P85 (P85), a potent inhibitor of P-glycoprotein (Pgp). P85 was radioactively labeled and administered intravenously (i.v.) to mice. The concentration of the copolymer was varied to examine the effects of micelle formation on the distribution kinetics. The main pharmacokinetic parameters (the area under the curve, half-life, clearance, mean residence time, and volume of distribution) were determined. The results suggest that half-life of P85 varies from 60 to 90 h, depending on its aggregation state. Formation of micelles decreased the uptake of the block copolymer in the liver. However, it had no effect on the total clearance, suggesting that the elimination of P85 was controlled by the renal elimination of P85 unimers and not by the rate of micelle disposition or disintegration. The total clearance value suggests that a significant portion of P85 is reabsorbed back into the blood, probably through the kidney's tubular membranes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Colloidal stability of aqueous dispersions of block ionomer complexes: effects of temperature and salt.

This work characterized colloidal stability of the dispersions, formed by the complexes of poly(ethylene oxide)-b-poly(sodium methacrylate) and hexadecyltrimethylammonium bromide. At room temperature, the dispersion was stabilized by the poly(ethylene oxide) (PEO) chains and did not aggregate for at least several months. Elevation of temperature caused aggregation of the dispersion because of dehydration of the PEO chains. At initial stages (minutes), the aggregation was reversible and the particles spontaneously redispersed once the temperature was decreased. However, it became irreversible at the later stages (hours), probably indicating fusion of the hydrophobic cores of the BIC particles. Addition of elementary salts led to a decrease of the aggregation temperature. The effects of various salts were dependent on the chemical nature of the ions and were consistent with the Hofmeister series. This behavior was discussed in terms of hydration and London (dispersion) interactions between the ions and the PEO.

Journal Article↗
PubMed2004

Micellar formulations for drug delivery based on mixtures of hydrophobic and hydrophilic Pluronic block copolymers.

Micelles formed by Pluronic block copolymers (PBC) have been studied in multiple applications as drug delivery systems. Hydrophobic PBC form lamellar aggregates with a higher solubilization capacity than spherical micelles formed by hydrophilic PBC. However, they also have a larger size and low stability. To overcome these limitations, binary mixtures from hydrophobic PBC (L121, L101, L81, and L61) and hydrophilic PBC (F127, P105, F87, P85, and F68) were prepared. In most cases, PBC mixtures were not stable, revealing formation of large aggregates and phase separation within 1-2 day(s). However, stable aqueous dispersions of the particles were obtained upon (1). sonication of the PBC mixtures for 1 or 2 min or (2). heating at 70 degrees C for 30 min. Among all combinations, L121/F127 mixtures (1:1% weight ratio) formed stable dispersions with a small particle size. The solubilizing capacity of this system was examined using a model water-insoluble dye, Sudan (III). Mixed L121/F127 aggregates exhibited approximately 10-fold higher solubilization capacity compared to that of F127 micelles. In conclusion, stable aqueous dispersions of nanoscale size were prepared from mixtures of hydrophobic and hydrophilic PBC by using the external input of energy. The prepared mixed aggregates can efficiently incorporate hydrophobic compounds.

Chemistry, Pharmaceutical↗
PubMed2004

Effect of pluronic P85 on ATPase activity of drug efflux transporters.

PURPOSE: Pluronic block copolymers are potent sensitizers of multi-drug resistant (MDR) cancer cells. The sensitization effect by Pluronics is a result of two processes acting in concert: i) intracellular ATP depletion, and ii) inhibition of ATPase activity of drug efflux proteins. This work characterizes effects of Pluronic P85 on ATPase activities of Pgp, MRP1, and MRP2 drug efflux transport proteins and interaction of these proteins with their substrates, vinblastine, and leucotriene C4. METHODS: Using membranes overexpressing Pgp, MRP1, and MRP2, the current study evaluates effects of Pluronic P85 (P85) on the kinetic parameters (Vmax, Km, Vmax/Km) of ATP hydrolysis by these ATPases. RESULTS: The decreases in the maximal reaction rates (Vmax) and increases in apparent Michaelis constants (Km) for these transporters in the presence of various concentrations of P85 were observed. The mechanism of these effects may involve i) conformational changes of the transporter due to membrane fluidization and/or ii) nonspecific steric hindrance of the drug-binding sites by P85 chains embedded into cellular membranes. The extent of these alterations was increased in the row MRP1 < MRP2 << Pgp. CONCLUSIONS: These data suggest that there are unifying pathways for the inhibition of Pgp and MRPs by the block copolymer. However, the effect of P85 on Pgp ATPase activity is considerably greater compared with the effects on MRP1 and MRP2 ATPases. This may be a reason for greater inhibitory effects of Pluronic in Pgp- compared with MRP-overexpressing cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Effects of pluronic P85 on GLUT1 and MCT1 transporters in the blood-brain barrier.

PURPOSE: The amphiphilic block copolymer Pluronic P85 (P85) increases the permeability of the blood-brain barrier (BBB) with respect to a broad spectrum of drugs by inhibiting the drug efflux transporter, P-glycoprotein (Pgp). In this regard, P85 serves as a promising component for CNS drug delivery systems. To assess the possible effects of P85 on other transport systems located in the brain, we examined P85 interactions with the glucose (GLUT1) and monocarboxylate (MCT1) transporters. METHODS: Polarized monolayers of primary cultured bovine brain microvessel endothelial cells (BBMEC) were used as an in vitro model of the BBB. 3H-2-deoxy-glucose and 14C-lactate were selected as GLUT1 and MCT1 substrates, respectively. The accumulation and flux of these substrates added to the luminal side of the BBMEC monolayers were determined. RESULTS: P85 has little effect on 3H-2-deoxy-glucose transport. However, a significant decrease 14C-lactate transport across BBMEC monolayers is observed. Histology, immunohistochemistry, and enzyme histochemistry studies show no evidence of P85 toxicity in liver, kidney, and brain in mice. CONCLUSIONS: This study suggests that P85 formulations do not interfere with the transport of glucose. This is, probably, due to compensatory mechanisms in the BBB. Regarding the transport of monocarboxylates, P85 formulations might slightly affect their homeostasis in the brain, however, without any significant toxic effects.

Animals↗
PubMed2004

Mixed polymer micelles of amphiphilic and cationic copolymers for delivery of antisense oligonucleotides.

Cationic copolymers were synthesized by conjugation of branched 2 kDa polyethylenimine (PEI) and Pluronic block copolymers (F38, P85, P123). Compositions of these copolymers mixed with corresponding free Pluronics at weight ratio 1:9 were used to complex phosphorothioate oligonucleotides (ODN). As a result stable suspensions of small micelle-like particles (<220 nm) were obtained. Incorporation of ODN in these formulations increased uptake of ODN in KBv cells and increased sequence specific activity of antisense ODN targeted against MDR gene in multidrug resistant cells resulting in inhibition of the functional activity of P-glycoprotein (P-gp) in these cells. Furthermore, these formulations increased transport of ODN across model intestinal barrier, Caco-2 cell monolayers, suggesting that they could be useful for oral delivery of biologically active ODN.

Caco-2 Cells↗