Modular transport platform for targeted delivery of therapeutic agents

摘要

The invention relates to a modular transport platform (MTP) configured to penetrate a target cell, deliver the MTP into the target cell, provide a pH dependent membrane disruption activity, direct intracellular transport into a target subcellular compartment of the target cell, and couple the active agent within the modular platform. The modular transport platform includes: (1) a ligand module to target a specific receptor on the surface of the target cell; (2) an endosomolytic module that provides pH-dependent membrane disruption activity within the target cell; (3) an intracellular transport module to cause delivery of the MTP to a particular subcellular compartment; (4) a module for intracellular retention; (5) a module for subcellular recognition; (6) a substance to be transported by the MTP; and (7) a carrier module for unifying the modules and coupling the modules with the transported substance.

主权项

1. A modular transport platform (MTP) comprising several functional polypeptide modules within one molecule, specifically configured to penetrate a target cell, deliver the modular transporting platform into the target cells, provide pH-dependent membrane disruption activity, directed intracellular transport into a target subcellular compartment of the target cell, and an active agent coupled within the modular transport platform, the molecule comprising:
a first, heterologous module for a non-covalent coupling and having a hydrophobic pocket, the first, heterologous module being an E. coli hemoglobin-like protein, HMP, prepared from a first sequence, and comprising a non-covalently coupled cyclic tetrapyrrol chlorin or chlorin derivative, wherein the chlorin or chlorin derivative is covalently coupled to the active agent, and the chlorin or chlorin derivative is inserted into the hydrophobic pocket in vitro; a second, heterologous module prepared from a second sequence and configured to cause delivery of the MTP to a particular subcellular compartment, wherein the intracellular transport module delivers the MTP to the subcellular compartment based on one or more cellular transport mechanisms; a third, heterologous module prepared from a third sequence and configured to prolong the localization of the modular transport platform within the target subcellular compartment by binding to a component within the subcellular compartment to retain the MTP within the subcellular compartment or by undergoing a chemical modification within the subcellular compartment to impede the ability of the MTP to be exported from the targeted subcellular compartment.