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Transferrin receptor-targeted redox/pH-sensitive podophyllotoxin prodrug micelles for multidrug-resistant breast
Yongfei Li1, Mie Chen2, Bowen Yao3
1Department of Mastopathy, The Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Province Hospital of TCM), No. 155 Hanzhong Road, Nanjing 210029, China. yaochang67@126.com.
Abstract:
Podophyllotoxin (PPT), a toxic polyphenol extracted from the roots of Podophyllum species, showed remarkable activity against P-glycoprotein (P-gp) mediated multidrug resistant (MDR) cancer cells. Many PPT-prodrugs based on nano-technology have been developed for increasing aqueous solubility and reducing the side effects of PPT; however, the sensitive linkers in almost all PPT-prodrugs were ester bonds, resulting in slow and incomplete drug release. We developed a redox/pH double-sensitive and tumor active targeted drug delivery system for PPT delivery, in which PPT was covalently coupled to T7-peptide (Pep) modified polyethylene glycol (PEG) or methoxy-polyethylene glycol (mPEG) through a disulfide bond to obtain the final polymer (Pep-PEG-SS-PPT or PEG-SS-PPT). The mixed micelles (Pep-SS-NPs) were made by mixing Pep-PEG-SS-PPT with PEG-SS-PPT, and the mixed micelles showed good size uniformity and high stability in serum solution. The in vitro release experiment showed that about (81.7 ± 2.8)% PPT was released from Pep-SS-NPs in 10 mM glutathione (GSH) at pH 7.4, and also about (64.6 ± 1.7)% PPT was released from Pep-SS-NPs at pH 5.0. In vitro cytotoxicity analysis suggested that Pep-SS-NPs exhibited 57- to 270-fold lower resistance index (RI) values for different drug-resistant cancer cell lines than paclitaxel (PTX) or docetaxel (DTX). The cell uptake assay indicated that the Pep-SS-NPs could significantly enhance the intracellular level of coumarin-6 compared to that of the control group. The maximum tolerated dose (MTD) of Pep-SS-NPs was increased greatly compared to that of free PPT (5.3-fold). In vivo research showed that Pep-SS-NPs significantly enhanced antitumor efficacy against MCF-7/ADR xenograft tumors compared to the control groups. These findings suggest that mixed micelles could be a potentially successful nanomedicine for MDR breast cancer therapy.
Insights
This study introduces a novel nanomedicine using podophyllotoxin (PPT) for multidrug-resistant (MDR) cancers. The new system enhances drug release and significantly improves anti-tumor efficacy in vivo, offering a promising therapy for MDR breast cancer.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Podophyllotoxin (PPT) exhibits activity against multidrug-resistant (MDR) cancer cells but faces challenges with solubility and side effects.
- Existing PPT-prodrugs often use ester bonds, leading to suboptimal drug release kinetics.
Purpose of the Study:
- To develop a redox/pH double-sensitive, tumor-targeted drug delivery system for PPT.
- To create mixed micelles (Pep-SS-NPs) for enhanced PPT delivery and efficacy against MDR cancer.
Main Methods:
- PPT was conjugated to T7-peptide (Pep) modified polyethylene glycol (PEG) via a disulfide bond.
- Mixed micelles were formed by combining Pep-PEG-SS-PPT and PEG-SS-PPT.
- In vitro release, cytotoxicity, cell uptake, and in vivo anti-tumor efficacy were evaluated.
Main Results:
- Pep-SS-NPs demonstrated efficient PPT release under both physiological (pH 7.4, GSH) and tumor-mimicking (pH 5.0) conditions.
- Pep-SS-NPs showed significantly lower resistance index values compared to paclitaxel and docetaxel.
- Enhanced cellular uptake and a 5.3-fold increase in maximum tolerated dose were observed.
- In vivo studies revealed significant anti-tumor efficacy against MCF-7/ADR xenograft tumors.
Conclusions:
- The developed mixed micelle system (Pep-SS-NPs) is a promising nanomedicine for treating MDR breast cancer.
- The redox/pH-sensitive disulfide bond and T7-peptide targeting enhance PPT delivery and therapeutic outcomes.
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