Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery
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AbstractOver-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (log P> 6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (log P= 1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a log. P of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-. b-polylactic acid (PEG-. b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-. b-PLA nanoparticles (DOX.NP) with mean particle size below 100. nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.
All Author(s) ListTam Y.T., To K.K.W., Chow A.H.L.
Journal nameColloids and Surfaces B: Biointerfaces
Volume Number139
PublisherElsevier BV
Place of PublicationNetherlands
Pages249 - 258
LanguagesEnglish-United Kingdom
KeywordsAmphiphilic diblock copolymer, Anticancer activity, Flash nanoprecipitation, Lipophilicity, Multidrug resistance, Polymer-stabilized doxorubicin nanoparticles, Polyvinylpyrrolidone, Slow release, Stability

Last updated on 2020-19-10 at 02:51