Multifunctional Liposomes Enable Active Targeting and Twinfilin 1 Silencing to Reverse Paclitaxel Resistance in Brain Metastatic Breast Cancer.

Abstract

Paclitaxel (PTX) is a first-line chemotherapeutic drug for breast cancer, but PTX resistance often occurs in metastatic breast cancer. In addition, due to the poor targeting of chemotherapeutic drugs and the presence of the blood-brain barrier (BBB), it is hard to effectively treat brain metastatic breast cancer using paclitaxel. Thus, it is urgent to develop an effective drug delivery system for the treatment of brain metastatic breast cancer. The current study found that TWF1 gene, an epithelial-mesenchymal transition-associated gene, was overexpressed in brain metastatic breast cancer (231-BR) cells and was associated with the PTX resistance of 231-BR cells. Knockdown of TWF1 by small interference RNA (siRNA) in 231-BR cells could effectively increase the sensitivity of brain metastatic breast cancer cells to paclitaxel. Then, a liposome-based drug delivery system was developed for PTX delivery across BBB, enhancing PTX sensitivity and brain metastases targeting via BRBP1 peptide modification. The results showed that BRBP1-modified liposomes could effectively cross the BBB, specifically accumulate in brain metastases, and effectively interfere TWF1 gene expression in vitro and in vivo, and thus they enhanced proliferation inhibition, cell cycle arrest, and apoptosis induction, thereby inhibiting the formation and growth of brain metastases. In summary, our results indicated that BRBP1-modified and PTX- and TWF1 siRNA-loaded liposomes have the potential for the treatment of brain metastatic breast cancer, which lays the foundation for the development of a new targeted drug delivery system.

• Authors: Jiawei Du, Yong Shao, Yue Hu, Yiwen Chen, Jiehui Cang, Xin Chen, Wenqin Pei, Fengqin Miao, Yuqing Shen, Mohd Muddassir, Ying Zhang, Jianqiong Zhang, Gaojun Teng
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 13 Issue 20 Pg. 23396-23409 (May 26 2021) ISSN: 1944-8252 [Electronic] United States
• PMID: 33982563 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BRBP1 peptide
• Liposomes
• Microfilament Proteins
• Oligopeptides
• RNA, Small Interfering
• TWF1 protein, human
• Protein-Tyrosine Kinases
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (genetics, metabolism, secondary)
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Liposomes (chemistry, pharmacokinetics)
• Mice
• Mice, Inbred BALB C
• Microfilament Proteins (genetics, metabolism)
• Nanoparticles (chemistry, metabolism)
• Oligopeptides (chemistry)
• Paclitaxel (chemistry, pharmacology)
• Protein-Tyrosine Kinases (genetics, metabolism)
• RNA, Small Interfering (genetics, pharmacokinetics, pharmacology)