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Dehydroascorbic Acid and pGPMA Dual Modified pH-Sensitive Polymeric Micelles for Target Treatment of Liver Cancer
1Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Abstract:
In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as lack of potency of tumor penetration. In this work, we developed actively tumor-targeting micelles with pH-sensitive linker as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable poly(ethylene glycol)-poly(aspartate) polymers, in which paclitaxel can be covalently conjugated to pAsp via an acid-labile acetal bond to form pH-responsive structures. In vitro drug release studies showed that these structures were stable in physiological condition, whereas collapsed once internalized into cells due to the mildly acidic environment in endo/lysosomes, resulting in facilitated intracellular paclitaxel release. In addition, dehydroascorbic acid and guanidinopropyl methacrylamide polymers were decorated on the surface of micelles to achieve specific tumor accumulation and tumor penetration. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
Insights
Novel pH-sensitive micelles loaded with paclitaxel show enhanced accumulation and penetration in hepatocellular carcinoma (HCC) tumors. This targeted drug delivery system improves anti-HCC efficacy, offering a promising platform for cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) prognosis is poor due to limited chemotherapeutic drug accumulation and penetration in tumors.
- Developing effective drug delivery systems is crucial for improving HCC treatment outcomes.
Purpose of the Study:
- To develop actively tumor-targeting micelles with pH-sensitive linkers as a novel nanocarrier for HCC therapy.
- To enhance intracellular drug release and improve anti-HCC efficacy.
Main Methods:
- Biodegradable poly(ethylene glycol)-poly(aspartate) polymers were used to create pH-responsive micelles.
- Paclitaxel was conjugated via an acid-labile acetal bond, and dehydroascorbic acid/guanidinopropyl methacrylamide polymers were added for targeting and penetration.
- In vitro drug release, cellular uptake, in vivo imaging, and anti-HCC efficacy studies were conducted.
Main Results:
- The micelles demonstrated stability in physiological conditions and collapsed in acidic endo/lysosomal environments, facilitating intracellular paclitaxel release.
- Surface modifications led to remarkable targeting of hepatocarcinoma cells and tumors.
- Enhanced anti-HCC efficacy was confirmed both in vitro and in vivo.
Conclusions:
- The developed micellar system exhibits significant tumor-targeting and penetration capabilities for HCC.
- This pH-sensitive nanocarrier platform shows potential for improved chemotherapeutics delivery in HCC treatment.