Abstract
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.
Highlights
Drug resistance of cancer cells is one of the main reasons for the failure of cancer treatment, which may lead to rapid recurrence or disease progression of cancer and result in death [1,2,3]
The drug resistance of the MCF-7/ADR cell line was verified by a resistance index (RI) value before the cytotoxicity experiment
The value of RI was 24.58, which indicated that MCF-7/ADR was resistant to PTX (Figure S1)
Summary
Drug resistance of cancer cells is one of the main reasons for the failure of cancer treatment, which may lead to rapid recurrence or disease progression of cancer and result in death [1,2,3]. We found that nanocrystals can act as the solid material on which dopamine polymerized to form PDA coating [32] Such a polydopamine film contains active catechol hydroxyl groups, which can further react with amino groups under mild conditions [38], which provided a good active reaction platform for functional modification of nanocrystals. CNC@PDA-PEG had a better therapeutic effect on a drug-resistant cancer cell line (MCF-7/ADR) compared to a simple mixture of PTX and LAPA. This delivery system provides a platform for synergic delivery of PTX and LAPA for the chemo-resistant breast tumor. PTX: paclitaxel; LAPA: lapatinib; cNC: composite nanocrystals; PDA: polydopamine; PEG: Polyethylene glycol
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