Polymer–Doxorubicin Conjugate Micelles Based on Poly(ethylene glycol) and Poly(<i>N</i>‑(2-hydroxypropyl) methacrylamide): Effect of Negative Charge and Molecular Weight on Biodistribution and Blood Clearance

Abstract

Well-defined water-soluble block copolymers poly­(ethylene glycol)-<i>b</i>-poly­(<i>N</i>-(2-hydroxypropyl) methacrylamide-<i>co</i>-<i>N</i>-methacryloylglycylglycine) (PEG-<i>b</i>-P­(HPMA-<i>co</i>-MAGG)) and their doxorubicin (Dox) conjugates with different composition and molecular weight were synthesized. These Dox conjugates can form micelles in buffer solution. The physicochemical properties, in vivo biodistribution, blood clearance, and especially the tumor accumulation of copolymers and micelles were studied. Severe liver accumulation can be observed for PEG-<i>b</i>-PMAGG copolymers. This was quite different from their Dox conjugate for which decreased RES uptake and elevated kidney accumulation could be observed. When decrease the negative charge to an appropriate amount such as 8–10 mol %, both RES uptake and kidney accumulation could be suppressed. Obvious tumor accumulation could be achieved especially when the molecular weight were increased from ∼40 to ∼80 KDa. These results provided us with a guideline for the design of nanoscaled drug delivery system as well as a potential option for treating kidney-related cancers