Organ-restricted vascular delivery of nanoparticles for lung cancer therapy.

Deniz A Bölükbas,Michael Lindner,Otmar Schmid,Silke Meiners,Stefan Datz,Lin Yang,Christian Argyo,Carmela Morrone,Ali Doryab,Malamati Vreka,Oliver Eickelberg,Sabine H Van Rijt,Sandra Lindstedt,Dorothee Gößl,Darcy E Wagner,Charlotte Meyer‐Schwickerath,Tobias Stoeger,Georgios T Stathopoulos,Thomas Bein

doi:10.1002/adtp.202000017

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.

Highlights

The use of nanoparticles as therapeutic agents for cancer therapy and other diseases has attracted major attention in the past decades
The internal pore system of the MSNs was functionalized with thiol groups and the external particle surface with amino groups, creating a nanoparticle platform which allows for a wide range of customizable functionalizations (Figure 2A)
Recent evidence suggests that previous reports may have overestimated the contribution of the enhanced permeability and retention (EPR) to directing nanoparticles to tumors and that additional active cellular processes, such as transcytosis, promote extravasation of nanoparticles into tumors.[16]

Summary

Introduction

The use of nanoparticles as therapeutic agents for cancer therapy and other diseases has attracted major attention in the past decades. The first generation of nanomedicines for cancer relied on passive targeting of cancer cells based on the concept of enhanced permeability and retention (EPR) effect observed in tumors.[1] The EPR effect has been described to promote preferential accumulation of nanoparticles in the tumor due to increased blood vessel permeability and impaired lymphatic drainage in the tumorous regions. Several FDA-approved nanomedicines have been designed with the intent of exerting their therapeutic effect by passive targeting of tumors.[2] More recently, nanoparticles incorporating active targeting strategies have emerged as an alternative approach to fine-tune nanoparticle delivery to specific cell types.[3] To achieve cellspecific targeting, nanoparticles can be functionalized with targeting agents on their surface, which can bind to receptors overexpressed on tumor or tumor-associated cells. The initial excitement accompanying these innovative nanomedical approaches has failed to translate into clinical success, largely due to physicochemical and biological factors which impair nanoparticle targeting in vivo.[5]

Methods

Results

Conclusion