A Novel Approach to Formulation of Anticancer Drugs in Nanoparticles.

Nanoparticle;Cancer;Ion-pair;Doxorubicin;Health Sciences;Pharmaceutical Sciences

Gu, XinyiYang, Victor Chi-Min ;

University of Michigan

关键词: Nanoparticle;    Cancer;    Ion-pair;    Doxorubicin;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/61624/gux_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Many anticancer drugs, due to their hydrophilicity, have poor drug loading in nanoparticles. Charge-charge interactions may be effective for improving loading where charges in nanoparticles attract oppositely charged drug molecules. A new strategy, incorporation of charged hydrophobic excipients into nanoparticles followed by drug loading via incubation, may effectively increase drug loading.First, hydrophobic alkyl sulfates were tested for improved loading of a model hydrophilic drug, doxorubicin hydrochloride (doxHCl). Ion pairing between alkyl sulfates and doxHCl yielded hydrophobic complexes and indicated favorable incorporation into hydrophobic nanoparticle cores. However, encapsulation into nanoparticles failed due to poor complex solubility in organic solvents.A more hydrophobic series of borate-based anionic excipients was then studied. Solubility studies found ethyl acetate to be a suitable organic solvent for dissolving borate-based excipients at high concentrations. One of the excipients, potassium tetrakis(4-chlorophenyl) borate (KTpClPB), was the best as it had characteristics suitable for extraction of doxHCl into a hydrophobic phase. A new incubation loading strategy was utilized for drug uptake into nanoparticles. Optimization of this process found maximizing free acid number of polymers, amount of KTpClPB used, and drug:nanoparticle ratio increased drug loading. Increasing incubation temperature increased polymer strand rearrangements and promoted drug uptake. PEGylation of nanoparticles reduced nanoparticle aggregation to promote drug uptake. Using the optimized incubation loading procedure, another model drug, vinblastine sulfate, also achieved high drug loading, demonstrating that this procedure may be more broadly applicable. Comparison of incubation loading with traditional drug loading procedures (O/W or W/O/W emulsions), found traditional drug loading produced half the loading relative to incubation loading due to limited drug extraction into organic phase of O/W emulsions and limited inner aqueous phase volume of W/O/W emulsions. In vitro drug release profiles were similar for all nanoparticles, and the presence of KTpClPB, despite charge attractions, failed to slow drug release.