the interplay of normalized tumor vasculature and nanoparticles

It’s been a while since the last post – busy times around here. However, I finally found a few spare moments to read some papers. One that popped out at me is a recent pub in Nature Nanotechnology entitled “Normalization of tumor blood vessels improves the delivery of nanomedicines in a size-dependent manner“. Rakesh Jain from Massachusetts General Hospital is the corresponding author, with contributions from a bunch of other folks, including Moungi Bawendi from MIT. The paper points out one of the main conundrums associated with delivery of therapeutics deep into a solid tumor (regardless of whether they are “nano” or not). Whereas the leaky vasculature, and the associated “enhanced permeability and retention” (EPR) effect can in principle increase the deposition of nanomedicines at the tumor, leaky vessels also lead to an increased interstitial fluid pressure within tumors, which hinders penetration through the tumor. Clearly, poor tumor distribution, and the associated gradients in drug concentration, are not conducive to good clinical outcomes.

However, it has been shown that vascular normalization, which reduces the leakiness of the vessels, can improve clinical outcomes (for traditional chemotherapies) in a number of cancer types, presumably due to better drug delivery and tumor distribution. Jain and co-workers sought to investigate whether this might be true for nanomedicines, which are typically thought to rely upon vascular leakiness for deposition. Would a decrease in the vessel pore size (via normalization with VEGF receptor blocking antibodies) decrease the penetration of nanoparticles?

The basic findings are perhaps not surprising, but are nonetheless very important. Nanoparticles (quantum dots, in this case) around 12-nm in diameter display much better tumor penetration than larger particles (following normalization of the vessels). The authors pointed out that this size is about the smallest that can benefit from the EPR effect, making the absolute particle size an important design consideration in the development of nanomedicines. Larger materials will always suffer from poor vascular escape and tumor penetration, while smaller particles may localize in healthy organs simply by virtue of the size cutoff associated with normal vessels in those organs. In our group, these things are obviously very important, and we are further interested in how particle modulus might change these design rules – hopefully we will have some answers in the near future.

Published by Andrew Lyon

Founding Dean, Fowler School of Engineering @ Chapman University. Formerly Dean of the Schmid College of Science and Technology @ Chapman.

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