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Organ-restricted vascular delivery of nanoparticles for lung cancer therapy
Deniz A Bölükbas1, Stefan Datz2, Charlotte Meyer-Schwickerath3
1Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, and Helmholtz Zentrum München, Munich, Germany. Member of the German Center for Lung Research (DZL), 81377 Munich, Germany; Lung Bioengineering and Regeneration, Dept of Experimental Medical Sciences, Stem Cell Centre, Wallenberg Center for Molecular Medicine, Lund University Cancer Centre (LUCC), Lund University, 22362 Lund, Sweden.
Abstract:
Nanoparticle-based targeted drug delivery holds promise for treatment of cancers. However, most approaches fail to be translated into clinical success due to ineffective tumor targeting in vivo. Here, the delivery potential of mesoporous silica nanoparticles (MSN) functionalized with targeting ligands for EGFR and CCR2 is explored in lung tumors. The addition of active targeting ligands on MSNs enhances their uptake in vitro but fails to promote specific delivery to tumors in vivo, when administered systemically via the blood or locally to the lung into immunocompetent murine lung cancer models. Ineffective tumor targeting is due to efficient clearance of the MSNs by the phagocytic cells of the liver, spleen, and lung. These limitations, however, are successfully overcome using a novel organ-restricted vascular delivery (ORVD) approach. ORVD in isolated and perfused mouse lungs of Kras-mutant mice enables effective nanoparticle extravasation from the tumor vasculature into the core of solid lung tumors. In this study, ORVD promotes tumor cell-specific uptake of nanoparticles at cellular resolution independent of their functionalization with targeting ligands. Organ-restricted vascular delivery thus opens new avenues for optimized nanoparticles for lung cancer therapy and may have broad applications for other vascularized tumor types.
Insights
Targeted nanoparticle delivery for lung cancer faces challenges. A novel organ-restricted vascular delivery method overcomes limitations, enabling effective nanoparticle uptake in tumors, independent of targeting ligands.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Nanoparticle-based drug delivery shows potential for cancer treatment.
- Clinical translation is hindered by ineffective in vivo tumor targeting.
Purpose of the Study:
- To investigate mesoporous silica nanoparticles (MSN) functionalized with EGFR and CCR2 ligands for lung tumor delivery.
- To evaluate the efficacy of organ-restricted vascular delivery (ORVD) for enhancing nanoparticle tumor targeting.
Main Methods:
- Systemic and local administration of MSNs with targeting ligands in murine lung cancer models.
- Evaluation of nanoparticle uptake in vitro and in vivo.
- Application of a novel organ-restricted vascular delivery (ORVD) approach in isolated and perfused mouse lungs.
Main Results:
- Targeting ligands enhanced MSN uptake in vitro but not in vivo tumor targeting.
- MSNs were cleared by phagocytic cells in the liver, spleen, and lungs.
- ORVD facilitated nanoparticle extravasation into lung tumors and promoted tumor cell-specific uptake, independent of targeting ligands.
Conclusions:
- Standard nanoparticle targeting strategies are limited by in vivo clearance and ineffective tumor accumulation.
- Organ-restricted vascular delivery (ORVD) is a promising strategy to overcome these limitations for lung cancer nanoparticle therapy.
- ORVD may offer broad applications for other vascularized tumor types.
