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Multistage Passive and Active Delivery of Radiolabeled Nanogels for Superior Tumor Penetration Efficiency
Natascha Drude1,2, Smriti Singh2, Oliver H Winz1
1Department of Nuclear Medicine, RWTH Aachen University , 52074 Aachen, Germany.
Abstract:
Development of nanosized drug delivery systems in cancer therapy is directed toward improving tumor selectivity and minimizing damages of healthy tissue. We introduce a delivery system with synergistic optimization and combination of passive and active targeting strategies. The approach is based on radiopeptide labeled redox sensitive hydrophilic nanogels, which exploit passive targeting by the enhanced permeability and retention effect while avoiding elimination by the mononuclear phagocyte system and fast hepatic and renal clearance. The targeting peptide promotes endocytotic uptake of the nanogels by cancer cells. Specific to this delivery system, tumor-specific degradation by the antioxidant glutathione enhances penetration and retention within the tumor tissue. Using in vivo molecular imaging we demonstrate the superiority of combined passive and active targeting with down-sizable nanogels over exclusive passive targeting. Furthermore, the homogeneous tumor distribution of functionalized nanogels compared to the clinically used mere radiopeptide supports the potentially high impact of our targeting concept.
Insights
This study introduces advanced nanogels for cancer therapy, combining passive and active targeting. This novel drug delivery system improves tumor selectivity and retention, outperforming traditional methods.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Developing targeted nanodrug delivery systems is crucial for enhancing cancer therapy efficacy.
- Current systems aim to improve tumor selectivity and minimize damage to healthy tissues.
- Overcoming rapid clearance and achieving sustained tumor retention remain key challenges.
Purpose of the Study:
- To develop and evaluate a novel nanogel-based drug delivery system for cancer therapy.
- To synergistically combine passive and active targeting strategies for improved tumor targeting.
- To investigate the role of tumor-specific degradation in enhancing nanogel penetration and retention.
Main Methods:
- Radiopeptide-labeled, redox-sensitive hydrophilic nanogels were synthesized.
- Passive targeting was achieved via the enhanced permeability and retention (EPR) effect.
- Active targeting utilized a peptide for cancer cell endocytosis, with glutathione-mediated degradation for enhanced tumor retention.
- In vivo molecular imaging was employed to assess biodistribution and tumor targeting efficacy.
Main Results:
- The combined passive and active targeting nanogels demonstrated superior tumor accumulation and retention compared to exclusive passive targeting.
- Nanogels avoided rapid clearance by the mononuclear phagocyte system, liver, and kidneys.
- Tumor-specific degradation by glutathione enhanced nanogel penetration and retention within the tumor microenvironment.
- Homogeneous tumor distribution of functionalized nanogels was observed, outperforming conventional radiopeptide therapy.
Conclusions:
- The developed nanogel system effectively combines passive and active targeting strategies for enhanced cancer therapy.
- Tumor-specific degradation is a key feature for improving nanogel penetration and retention in solid tumors.
- This synergistic approach holds significant potential for improving the efficacy and safety of nanomedicine in oncology.
