Folic Acid and Poly(ethylene glycol) Decorated Paclitaxel Nanocrystals Exhibit Enhanced Stability and Breast Cancer-Targeting Capability
Jihui Zhao, Jianliang Du, Jun Wang, Na An, Kuan Zhou, Xiaoge Hu, Zhiying Dong, Yu Liu
Abstract
In part because of their high drug loading, nanocrystals (NCs) have seen extensive use in drug delivery, particularly for insoluble or poorly soluble drugs. It remains a challenge, however, to prepare stable nanocrystals with tumor-targeting capability. Here, we designed a novel preparation of stable paclitaxel (PTX) nanocrystals with efficient active tumor-targeting properties. PTX NC was prepared using a bottom-up method and modified with both poly(ethylene glycol) (PEG) and folic acid (FA) derivatives using film hydration. The resulting PTX NC@lipid–PEG–FA had a rodlike shape, with hydrodynamic diameters and drug loading values of 201.90 ± 2.92 nm and 31.07 ± 3.41%, respectively. The size of the PTX NC@lipid–PEG–FA was unchanged after 168 h in the presence of plasma, whereas nonmodified paclitaxel nanocrystals (PTX NC) exceeded 600 nm within 12 h under the same conditions. Cellular uptake and cellular growth inhibition experiments in 4T1 breast cancer cells showed the superiority of PTX NC@lipid–PEG–FA over PTX NC or PEGylated paclitaxel nanocrystals without FA modification (PTX NC@lipid–PEG). A pharmacokinetic evaluation in rats revealed that PTX NC@lipid–PEG–FA significantly prolonged the circulation of PTX in the bloodstream, in comparison with PTX NC or Taxol. Tissue distribution and in vivo antitumor studies in 4T1 orthotopic breast cancer-bearing nude mice showed that PTX NC@lipid–PEG–FA significantly increased the intratumor accumulation of PTX and efficiently inhibited tumor growth, in comparison with PTX NC@lipid–PEG, PTX NC, or Taxol. In summary, PTX NC@lipid–PEG–FA showed good potential for breast cancer-targeted delivery for insoluble therapeutics.