Concept And Design

We designed a macromolecular carrier system so that the macromolecular conjugate could utilize EPR effect efficiently by an extremely long retention of its high plasma-levels (Fig. 1), and so that it could show a drug-release rate appropriate to a parent drug applied to the system in tumor tissue without releasing the drug in bloodstream.

Figure J. Passive tumor-targeting based on EPR effect.

Peptidyl spacer was used for releasing the parent drug from the conjugate by lysosomal enzymes of cathepsins after its uptake into cells. The longer retention of the conjugate in bloodstream should lead it to a more preferential tumor-accumulation, in proportion to its levels of tumor vascular permeability, and the control of drug-release should bring out the best in the parent drug applied to the system. For this DDS concept, as described in section 1, we selected a stealthy and biodegradable carrier, CM-Dex-PA, with molecular sizes larger than the renal threshold, and a peptidyl spacer, GGFG, to provide a slow release of the parent drug DX-8951 with a time-dependent cytocidal activity. The PA carrier with a high structural-flexibility and hydrophilicity was also suggested to have some capability of maintaining its stealthy property even after conjugation with the hydrophobic drug, differing from non-PA-polysaccharide carriers.

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