A new class of drug carriers: micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcontainers for drug targeting from blood in brain☆

Abstract A new concept of design of drug delivery systems based on using self-assembling supramacromolecular complexes is formulated. Microcontainers for drug targeting were prepared using polymeric surfactant poly(oxyethylene)-poly(oxypropylene) block copolymer (pluronic). Molecules of a drug are solubilized in a pluronic micelle being incorporated into its inner hydrophobic core, formed by poly(oxypropylene) chain blocks. The outer hydrophilic shell of such micelles is formed by nontoxic and nonimmunogenic poly(oxyethylene) blocks. Solubilization of low molecular weight compounds (fluorescein isotbiocyanate (FITC), haloperidol etc.) in pluronic micelles was studied using fluorescence and ultracentrifugation. The dimensions of the aggregates formed in the solutions of various pluronics (P85, F64, L68, L101) and its mixtures were determined using quasielastic light-scattering technique. In a majority of cases the diameter of pluronic micelles (including those containing solubilized compounds) was in the range of 12–36 nm. For targeting of such microcontainers to a certain cell the pluronic molecules were conjugated with antibodies against a target-specific antigen or with protein ligands selectively interacting with target cell receptors. The obtained conjugates were then incorporated into the drug-containing micelles by simple mixing of the corresponding components. It was found that solubilization of FITC in pluronic micelles considerably influences its distribution in animal (mouse) tissues resulting, in particular, in the drastic increase of FITC fluorescence in lung. Conjugation of FITC-containing micelles with insulin vector results in increase of FITC penetration in all tissues including the brain. The specific targeting of the solubilized FITC in brain was observed in the case when the pluronic conjugate with antibodies to the antigen of brain glial cells ( α 2 -glycoprotein) was incorporated into micelles. Under these conditions the considerable increase of FITC fluorescence in the brain and decrease of its fluorescence in the lungs has been registered. Possibility of using micellar microcontainers for targeting of solubilized neuroleptics (haloperidol) in brain was studied. Incorporation of antibodies to α 2 glycoprotein into haloperidol-containing micelles results in a drastic increase of drug effect. This result indicates that vector-containing pluronic micelles provide an effective transport of solubilized neuroleptics across blood-brain barrier.