Expandible microparticle intracellular delivery system

Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...

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4353201, 524560, 5263297, C12N 1564

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059522321

ABSTRACT:
The present invention relates to methods and compositions for delivery of a compound, most preferably a polynucleotide, into the cytoplasm of a cell by means of a microparticle, fabricated from a pH-sensitive hydrogel in collapsed phase, and having a size and physical characteristics compatible with uptake via a clathrin-coated pit on the cell surface. The trigger pH at which the hydrogel expands is lower than the physiological pH of the extracellular environment, allowing the microparticle, which comprises the compound to be delivered, to maintain its compact size prior to cellular uptake, thereby providing the additional benefit of protecting the comprised compound from degradation. This protective feature is particularly beneficial in embodiments in which a polynucleotide or a peptide is being delivered. Following uptake via a clathrin-coated pit, the microparticle then enters the intracellular endocytic pathway, where it is subjected to a progressive decrease in pH. Once the trigger pH for the hydrogel is reached, the microparticle increases its water content and expands, bursting its containing vesicle, and allowing its comprised compound to enter the cytoplasm. According to the invention, microparticle expansion and drug release may be achieved by natural mechanisms without requiring the addition of exogenous compounds, or the application of electric fields, etc. Moreover, with regard to embodiments involving polynucleotides, the present invention provides a means for traversing the plasma membrane and delivering the polynucleotide into the cytoplasm; in conventional transfection methods the plasma membrane, as well as intracellular membranes as occur in endosomes or lysosomes, constitute a formidable barrier to entry.

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