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Understanding the structure and stability of paclitaxel nanocrystals.

ABSTRACT: Previously, PTX/Pluronic F127 nanocrystals were prepared in our laboratory using the stabilization of nanocrystals (SNC) method. For PTX nanocrystals, dosages could be increased to yield improved antitumor activity over Taxol without incidence of acute toxicity. The objectives of this current study are to further understand the structure and stability of PTX nanocrystals. More Pluronic F127 surfactant was added in the formulation to attempt to further stabilize the nanocrystals against thermal induced aggregation. However, this resulted in formation of micelles that worsened the stability of nanocrystals. The F127 desorption experiment suggested different surfactant adsorption affinity to nanocrystal surface below and above the CMC. Below the CMC monomers bound to nanocrystal surface with high affinity, but above the CMC low affinity surfactant aggregates readily left the surface upon dilution. At higher temperature the tendency of F127 micellization is enhanced due to drastically lower CMC. Consequently, at 37 degrees C there was F127 desorption even for nanocrystals prepared with low amounts of F127 (1:5 (w/w) PTX/F127). To improve the stability of nanocrystals, re-nanonization by incubation-sonication procedure was used to disrupt the preferred crystal growth pattern of PTX. Furthermore, we have demonstrated that a higher heating temperature (45 degrees C vs. 37 degrees C) used in the incubation-sonication procedure was able to provide even better nanocrystal stability for long periods of incubation time.

SUBMITTER: Deng J

PROVIDER: S-EPMC3685190 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Understanding the structure and stability of paclitaxel nanocrystals.

Deng Jiexin J Huang Leaf L Liu Feng F

International journal of pharmaceutics 20100216 2

Previously, PTX/Pluronic F127 nanocrystals were prepared in our laboratory using the stabilization of nanocrystals (SNC) method. For PTX nanocrystals, dosages could be increased to yield improved antitumor activity over Taxol without incidence of acute toxicity. The objectives of this current study are to further understand the structure and stability of PTX nanocrystals. More Pluronic F127 surfactant was added in the formulation to attempt to further stabilize the nanocrystals against thermal i ...[more]

PMID: 20167270

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Project description:Drug resistance presents serious difficulties for cancer treatment. A combination of paclitaxel (PTX) and lapatinib (LAPA) shows potentials in multiple drug resistant cancers in the clinic, but it is almost impossible to deliver these two drugs to the tumor at the same time with the best proportion by simple co-administration of the respective current formualtions for their different pharmacokinetic profiles. Here composite nanocrystals of PTX and LAPA (cNC) were designed with a ratio of 2:1 (w/w), which was their intracellular ratio at the best synergistic efficacy on a drug-resistant cancer cell line (MCF-7/ADR). Such cNC were prepared using a bottom-up method to achieve a nearly spherical appearance and a narrow size distribution of 95.1 ± 2.1 nm. For nanocrystal stabilization, Polyethylene glycol (PEG) coating was introduced into the cNC via polydopamine (PDA) coating in order to get a PEGylated composite nanocrystal (cNC@PDA-PEG) with nanoscale size (170.5 ± 1.4 nm), considerable drug loading (PTX: 21.33 ± 1.48%, LAPA: 10.95 ± 1.24%) and good stability for at least 4 days in plasma-containing buffers. Differential scanning calorimeter (DSC) and XRD data both indicated the different crystalline states of the cNC as well as the cNC@PDA-PEG in comparison with bulk drugs. In vitro release data showed that PTX and LAPA were gradually and completely released from cNC@PDA-PEG in 3 days, while drug release from bulk drugs or cNC was only 30%. cNC@PDA-PEG also showed negligible hemolysis in vitro. Cellular uptake experiments in the MCF-7/ADR cell line showed that the nanocrystals entered the cells in a complete form through endocytosis and then released the drug in the cell. cNC@PDA-PEG inhibits the growth of this drug-resistant cell more effectively than the unmodified version (cNC). In summary, PEGylated PTX and LAPA composite nanocrystals showed the potential for treament of drug-resistant tumors by simultaneously delivering two drugs to tumor cells with the best proportion.

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Understanding the structure and stability of paclitaxel nanocrystals.

Publications

Understanding the structure and stability of paclitaxel nanocrystals.

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