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Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM-camptothecin
Pengkai Ma1, Yi Sun2, Jianhua Chen1
1a School of Chinese Materia Medica , Beijing University of Chinese Medicine , Beijing , China.
Abstract:
The efficient targeting of drugs to tumor cell and subsequent rapid drug release remain primary challenges in the development of nanomedicines for cancer therapy. Here, we constructed a glucose transporter 1 (GLUT1)-targeting and tumor cell microenvironment-sensitive drug release Glucose-PEG-PAMAM-s-s-Camptothecin-Cy7 (GPCC) conjugate to tackle the dilemma. The conjugate was characterized by a small particle size, spherical shape, and glutathione (GSH)-sensitive drug release. In vitro tumor targeting was explored in monolayer (2D) and multilayer tumor spheroid (3D) HepG2 cancer cell models (GLUT1+). The cellular uptake of GPCC was higher than that in the control groups and that in normal L02 cells (GLUT1-), likely due to the conjugated glucose moiety. Moreover, the GPCC conjugate exhibited stronger cytotoxicity, higher S arrest and enhanced apoptosis and necrosis rate in HepG2 cells than control groups but not L02 cells. However, the cytotoxicity of GPCC was lower than that of free CPT, which could be explained by the slower release of CPT from the GPCC compared with free CPT. Additional in vivo tumor targeting experiments demonstrated the superior tumor-targeting ability of the GPCC conjugate, which significantly accumulated in tumor meanwhile minimize in normal tissues compared with control groups. The GPCC conjugate showed better pharmacokinetic properties, enabling a prolonged circulation time and increased camptothecin area under the curve (AUC). These features contributed to better therapeutic efficacy and lower toxicity in H22 hepatocarcinoma tumor-bearing mice. The GLUT1-targeting, GSH-sensitive GPCC conjugate provides an efficient, safe and economic approach for tumor cell targeted drug delivery.
Insights
A novel glucose transporter 1 (GLUT1)-targeting nanomedicine conjugate (GPCC) demonstrates enhanced tumor cell uptake and efficacy. This conjugate offers a safer and more effective approach for cancer therapy by improving drug delivery and reducing toxicity.
Area of Science:
- Nanomedicine
- Cancer Therapy
- Drug Delivery Systems
Background:
- Efficient drug targeting and release in nanomedicines for cancer therapy face significant challenges.
- Glucose transporter 1 (GLUT1) is overexpressed in many cancer cells, presenting a potential target for drug delivery.
- Tumor microenvironment-specific drug release is crucial for enhancing therapeutic efficacy and minimizing off-target effects.
Purpose of the Study:
- To construct and evaluate a novel nanomedicine conjugate targeting GLUT1 and sensitive to the tumor microenvironment.
- To investigate the in vitro and in vivo targeting, drug release, and therapeutic efficacy of the developed conjugate.
- To assess the pharmacokinetic properties and toxicity profile of the nanomedicine for cancer treatment.
Main Methods:
- Development of a Glucose-PEG-PAMAM-s-s-Camptothecin-Cy7 (GPCC) conjugate with GLUT1-targeting and glutathione (GSH)-sensitive release.
- In vitro evaluation using HepG2 (GLUT1+) and L02 (GLUT1-) cancer cell models (2D and 3D spheroids) for cellular uptake, cytotoxicity, cell cycle arrest, apoptosis, and necrosis.
- In vivo studies in H22 hepatocarcinoma tumor-bearing mice to assess tumor targeting, pharmacokinetics, therapeutic efficacy, and toxicity.
Main Results:
- The GPCC conjugate exhibited small particle size, spherical shape, and GSH-sensitive drug release.
- Enhanced cellular uptake and cytotoxicity in GLUT1+ HepG2 cells compared to GLUT1- L02 cells and control groups.
- Superior in vivo tumor targeting, prolonged circulation time, increased drug exposure (AUC), improved therapeutic efficacy, and reduced toxicity in tumor-bearing mice.
Conclusions:
- The developed GLUT1-targeting and GSH-sensitive GPCC conjugate effectively delivers drugs to tumor cells.
- GPCC demonstrates promising therapeutic potential with enhanced efficacy and a favorable safety profile for cancer treatment.
- This nanomedicine approach offers an efficient, safe, and economical strategy for targeted cancer drug delivery.
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