1: J Control Release.  2003 Sep 19;92(1-2):19-26.  

A computationally derived structural model of doxorubicin interacting with
oligomeric polyalkylcyanoacrylate in nanoparticles.

Poupaert JH, Couvreur P.

Medicinal Chemistry, School of Pharmacie, Universite Catholique de Louvain UCL,
Avenue E. Mounier 73 (CMFA 7340), B-1200 Brussels, Belgium.
poupaert@cmfa.ucl.ac.be

We report a molecular simulation study of doxorubicin interacting within a frame
of n-butyl polycyanoacrylate, one of the most commonly encountered polymers in
the production of nanoparticles. Emphasis is put on the tetrameric, hexameric
and octameric oligomers (PACA's). Log P was calculated for all interacting
species. Molecular dynamics along with energy minimization processes (molecular
mechanics MM2, semi-empirical quantum mechanics PM3) were employed to probe the
conformational behavior of doxorubicin and polyalkylcyanoacrylate both as
isolated species and interacting with each other. A docked structure of
protonated doxorubicin with two octamers of n-butyl polycyanoacrylate is
described. Among the main stability factors of the assembly was the
charge-dipole interaction representing a stabilizing contribution of -33
kcal/mol. The mechanism of aggregation and desegregation (doxorubicin release)
can be summarized as follows: oligomeric PACA's are lipophilic entities that
scavenge amphiphilic doxorubicin already during the polymerization process by
extraction of the protonated species from the aqueous environment to the
increasingly lipophilic phase of the growing PACA's. The establishment of
hydrogen bonds between the ammonium N-H function and the cyano groups is
noteworthy. The cohesion in PACA nanoparticle comes therefore from a blend of
dipole-charge interaction, H bonds, and hydrophobic forces,

PMID: 14499182 [PubMed - in process]