Transvascular penetration of therapeutic nanoparticles (NPs) into the tumor mesenchymal space is critical for the treatment of solid tumors. Endothelial cells form the inner layer of blood vessels and are the main barrier regulating the entry of fluids, macromolecules, and immune cells into the mesenchymal space. Nanoparticles can bypass the endothelial barrier through active transendothelial or passive parietal endothelial transport pathways.
NPs are tumor-targeted and can be enriched in tumor tissues, also known as the high permeability and retention effect (EPR effect) in solid tumors. However, in most cases, only a small fraction (usually less than 5%) of nanoparticles can reach the mesenchymal regions of the tumor. Although active cytophagy or disruption of endothelial cell-cell junctions can open up intra-endothelial transport pathways, these mechanisms still do not fully explain why nanoparticles do not enter the tumor sufficiently.
This raises the question: are there other barriers besides the endothelial barrier that have been overlooked?
On September 14, 2023, Professor Yucai Wang's team at the University of Science and Technology of China published a research paper in the journal Nature Nanotechnology entitled "Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumors".
The study demonstrated that, in addition to the endothelial barrier, the tumor vascular basement membrane (BM) surrounding the endothelium also serves as a strong mechanical barrier, trapping NPs in the subendothelial space to form a pool of perivascular nanoparticles. Breaking this basement membrane barrier can greatly increase nanoparticle extravasation.
Taking advantage of the inflammation triggered by local thermotherapy, the team developed a synergistic immune-driven strategy to overcome the basement membrane barrier, resulting in robust tumor killing. Thermotherapy-induced platelet aggregation and inflammation recruited neutrophils into the nanoparticle pool. Subsequent movement of neutrophils through the basement membrane can release nanoparticles trapped in the subendothelial space, leading to nanoparticle entry into deeper tumors.
This study hints at the need to consider the tumor vascular basement membrane barrier when administering nanotherapies, and understanding this barrier will help develop more effective anti-tumor nanotherapies.
The basement membrane encases the endothelial and mural cells of the tumor vasculature, and it plays a crucial role in maintaining physicochemical and biological integrity. The basement membrane is a dense, cross-linked, sheet-like extracellular matrix that lies beneath the endothelium. In normal vessels, the basement membrane provides mechanical support and serves as a basic barrier for selective filtration of molecules or cells into interstitial tissues.
However, the basement membrane of neoplastic vessels has distinct structural abnormalities, including loose binding to endothelial and pericytes, extensive extension away from the vessel wall, and thickened layers. Although the basement membrane is critical, its role in impeding the entry of nanoparticles into the tumor mesenchyme is unclear.
While there are indications that the tumor vasculature is not leaking as previously predicted, the expected lack of leakage may not necessarily come from the endothelium alone. In this latest study, the team found that the tumor vascular basement membrane works hand-in-hand with the tumor endothelium to provide a strong barrier for nanoparticles to leave the tumor vascular system.
This study demonstrated that more than 92% of the basement membrane covers blood vessels in multiple tumor models and that the basement membrane acts as a previously overlooked physiological barrier to prevent nanoparticles from attempting to enter the tumor. After crossing the endothelial barrier, nanoparticles are blocked from forming perivascular nanoparticle pools in the subendothelial space.
In the context of antitumor nanomedicines, this basement membrane-induced nanoparticle pooling phenomenon actually prevents nanomedicine access to the tumor altogether.
Using a multi-step strategy, the team released pooled nanoparticles directly into the tumor from the basement membrane-based blockade. Through localized heat therapy (LHT), the team demonstrated that disruption of vascular endothelial (VE)-calmodulin interactions can lead to an increase in nanoparticle pooling around tumor vessels. Recruited neutrophils open the basement membrane barrier during infiltration, releasing trapped nanoparticles from the pool in a series of repeatable "bursts" that penetrate deeply and efficiently into the tumor.
This study suggests that the basement membrane represents a neglected but important nanoparticle barrier that warrants further study to develop engineered strategies to overcome or maintain this barrier when necessary. The study also challenges the classical EPR effect and proposes a new theory of nanomedicine tumor delivery.