By targeting CD44 receptors, inhibiting
multidrug resistance (MDR),
controlling drug release, and synergistically inhibiting tumor growth,
a multilayered nanosystem was developed to serve as a multifunctional
platform for the treatment of drug-resistant breast cancers. The multilayer
nanosystem is composed of a poly(lactic-co-glycolic
acid) core, a liposome second layer, and a chitosan third layer. The
chitosan-multilayered nanoparticles (Ch-MLNPs) can co-deliver three
chemotherapeutic agents: doxorubicin (DOX), paclitaxel (PTX), and
silybin. The three drugs are released from the multilayered NPs in
a controlled and sequential manner upon internalization and localization
in the cellular endosomes. The presence of a chitosan layer allows
the nanosystem to target a well-characterized MDR breast cancer biomarker,
the CD44s receptor. In vitro cytotoxicity study showed that the nanosystem
loaded with triple drugs, DOX–PTX–silybin, resulted
in better antitumor efficacy than the single-drug or dual-drug nano-formulations.
Likely attributed to the MDR-inhibition effect of silybin, the co-delivered
DOX and PTX exhibited a better synergistic effect on MDR breast cancer
cells than on non-MDR breast cancer cells. The in vivo study also
showed that the multilayered nanosystem promoted MDR inhibition and
synergy between chemotherapeutic agents, leading to significant tumor
reduction in a xenograft animal model. Ch-MLNPs reduced the tumor
volume by fivefold compared to that of the control group without causing
overt cytotoxicity.