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An epirubicin-conjugated nanocarrier with MRI function to overcome lethal multidrug-resistant bladder cancer
Hung-Wei Yang1, Mu-Yi Hua, Hao-Li Liu
1Chang Gung Molecular Medicine Research Center, Department of Chemical and Materials Engineering, Chang Gung University, Kuei-Shan, Tao-Yuan 33302, Taiwan, ROC.
Abstract:
Multidrug resistance (MDR) presents a major obstacle to curing cancer. Chemotherapy failure can occur through both cell membrane drug resistance (CMDR) and nuclear drug resistance (NDR), and anticancer effectiveness of chemotherapeutic agents is especially reduced by their nuclear export. Here we report an exciting magnetically-targeted nanomedicine formed by conjugation of epirubicin (EPI) to non-toxic and high-magnetization nanocarrier (HMNC). Strikingly, HMNC-EPI overcomes both CMDR and NDR in human bladder cancer cell models, without using P-glycoprotein (P-gp) and nuclear pore inhibitors. Besides, the half-life of drug is prolonged ~1.8-fold (from 45 h to 81 h) at 37 °C, with a ~10-fold increase in concentration at the tumor site through magnetic targeting (MT). Moreover, malignant NDR bladder cancer can be effectively inhibited after 14 days in mice by just two injections and MT. We are the first to demonstrate the nanomedical strategy that can overcome the CMDR and NDR bladder cancers simultaneously, and proceed to the excellent MT therapy, significantly reducing the dosage and cardiotoxicity and holding great promise for incurable human MDR bladder cancer.
Insights
This study introduces a novel magnetically-targeted nanomedicine that overcomes multidrug resistance (MDR) in bladder cancer. The nanomedicine effectively targets and inhibits both cell membrane and nuclear drug resistance, offering a promising new therapy.
Area of Science:
- Oncology
- Nanomedicine
- Biotechnology
Background:
- Multidrug resistance (MDR) significantly hinders cancer chemotherapy efficacy.
- Chemotherapy failure involves cell membrane drug resistance (CMDR) and nuclear drug resistance (NDR), particularly due to nuclear export.
- Existing treatments often struggle to overcome both CMDR and NDR simultaneously.
Purpose of the Study:
- To develop a magnetically-targeted nanomedicine to overcome both CMDR and NDR in bladder cancer.
- To enhance the therapeutic effectiveness of epirubicin (EPI) by conjugating it to a high-magnetization nanocarrier (HMNC).
- To evaluate the efficacy of this nanomedicine in preclinical models of human bladder cancer.
Main Methods:
- Conjugation of epirubicin (EPI) to a non-toxic, high-magnetization nanocarrier (HMNC) to form HMNC-EPI.
- Utilizing magnetic targeting (MT) to concentrate the nanomedicine at the tumor site.
- Assessing the nanomedicine's ability to overcome CMDR and NDR in human bladder cancer cell models and in vivo mouse models.
Main Results:
- HMNC-EPI successfully overcomes both CMDR and NDR in human bladder cancer models without additional inhibitors.
- The drug's half-life was extended by approximately 1.8-fold, and tumor site concentration increased ~10-fold via MT.
- Two injections with MT effectively inhibited malignant NDR bladder cancer in mice over 14 days.
Conclusions:
- This nanomedical strategy is the first to simultaneously overcome CMDR and NDR in bladder cancer.
- The developed magnetically-targeted nanomedicine offers an effective therapy with reduced dosage and cardiotoxicity.
- This approach holds significant promise for treating incurable human MDR bladder cancer.
