Synergistic Antitumor Effects on Drug-Resistant Breast Cancer of Paclitaxel/Lapatinib Composite Nanocrystals

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.

Nanocrystals Slow-Releasing Ropivacaine and Doxorubicin to Synergistically Suppress Tumor Recurrence and Relieve Postoperative Pain

“…Similar nanocrystal complex formed by the cocrystallization of two or more drugs have been proven to effectively increase drug efficacy and reduce toxicity compared with a single drug . However, preparation of previously reported nanocrystal complexes usually involves the use of a toxic organic solvent with a time-consuming and complicated process. − In this study, homogeneous nanocrystal complexes could be easily obtained by using a self-assembling peptide to control the crystallization process of RVC and DOX, indicating a facile strategy for fabricating composite drug nanocrystals.…”

ZIF-8 integrated with polydopamine coating as a novel nano-platform for skin-specific drug delivery

“…The reason for the decrease in stability might be that the PDA layer could produce adhesiveness and noncovalent interactions such as hydrogen bonding, and π–π stacking, resulting in the possible aggregation and size increase of nanoparticles. 47 For improving the long-term storage stability of 5-FU@ZIF-8@PDA in practical use, they could be stored in dry form. Furthermore, the stability of the nanoparticles during the skin penetration experiment was investigated as well, and the result is shown in Fig.…”

Progress of Drug Nanocrystal Self-Stabilized Pickering Emulsions: Construction, Characteristics In Vitro, and Fate In Vivo

“…The dissolution of nanocrystals results in the release and subsequent dissolution of the probes in water, which enables unrestricted motion of the probe molecules and extinguishes the fluorescence. By hybridizing TPE with paclitaxel nanocrystals, Li’s group demonstrated that intact nanocrystals of paclitaxel could be internalized by HT-29 and KB cells [ 86 ]. The molecular dynamics of the uptake and exocytosis of THPE nanocrystals by KB cells in their own crystalline and molecular forms was further investigated [ 87 ].…”