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Treating metastatic cancer with nanotechnology

Key Points

  • In most patients, by the time cancer is detected, metastasis has already occurred. More than 80% of patients diagnosed with lung cancer, for example, present with metastatic disease.

  • Nanotechnology is not alien to the clinic; more than 40 nanotherapeutics have reached patients, including anticancer drugs and imaging agents.

  • Many current therapies are not reaching the sites of metastases. Nanomaterials have the potential to combine multiple therapeutic functions into a single platform, can be targeted to specific tissues and can reach particular subcellular compartments.

  • Primary targeting is the act of steering nanoparticles to the specific organ or organs in which the metastases reside.

  • Secondary targeting is the direction of these delivered materials to the cancer cells and potentially to a specific subcellular location within the cancer cell.

  • Many solid tumours exhibit the enhanced permeation and retention (EPR) effect through which nanomaterials may accumulate and be retained in the tumour. However, this effect is limited to tumours larger than 4.6 mm in diameter, hindering its use for targeting small, unvascularized metastases.

  • To treat the complex problem of metastatic cancer, we must combine the expertise of engineers, biologists and clinicians.

Abstract

Metastasis accounts for the vast majority of cancer deaths. The unique challenges for treating metastases include their small size, high multiplicity and dispersion to diverse organ environments. Nanoparticles have many potential benefits for diagnosing and treating metastatic cancer, including the ability to transport complex molecular cargoes to the major sites of metastasis, such as the lungs, liver and lymph nodes, as well as targeting to specific cell populations within these organs. This Review highlights the research, opportunities and challenges for integrating engineering sciences with cancer biology and medicine to develop nanotechnology-based tools for treating metastatic disease.

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Figure 1: The steps of metastasis and opportunities for therapeutic intervention.
Figure 2: Nanomaterial strategies from the point-of-view of the cell.
Figure 3: Metastatic spread to different organs.
Figure 4: The enhanced permeation and retention (EPR) effect.

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Acknowledgements

The authors thank R. Weinberg, R. Weissleder, J. Kolodny, C. A. Alabi, B. Chertok, V. Frenkel and D. Siegwart for helpful discussions. A.S. thanks the Misrock Foundation and D.A.H. thanks the Damon Runyon Cancer Research Foundation for postdoctoral support. M.M.W. thanks the US National Institutes of Health (NIH; grant K99-CA151968). J.D. thanks the National Defense Science and Engineering Graduate fellowship, National Science Foundation and MIT Presidential Fellowships for support as well as A. Bell and J. Haught for motivation. The authors thank the MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNE) for NIH grants U54CA151884 and EB000244.

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Glossary

Shear rates

The velocity gradient that is the relative velocity at which one layer of the fluid flows over an adjacent layer of the fluid.

Kupffer cells

A type of macrophage that lines the sinusoid walls of the liver and that removes toxins present in blood coming from the digestive tract. Involved in the breakdown and recycling of red blood cells and haemoglobin.

Phage display

A selection technique in which a library of peptide or protein variants is expressed on the outer membrane of virus-infected bacteria (phage virion) and then screened for binding affinity using a process called panning.

Ribosome display

A selection technique in which diverse gene sequences encoding functional proteins are produced by ribosomes and then screened for their affinity to bioactive targets using a process called panning.

Aptamers

Oligonucleotides with high binding affinity to proteins or other molecules.

Peptide nucleic acids

Artificial polymers that mimic the DNA or RNA base structure, but that replace the negatively charged deoxyribose and ribose sugar backbone with N-(2-aminoethyl)-glycine units linked by peptide bonds.

DNA origami cages

The specificity between complementary DNA base pairs enables constructing nanoscale architectures using a combination of predesigned long and short DNA strands.

Filomicelles

Worm-like micelles that are composed mainly of biodegradable materials that can reach up to several microns in length and that can remain in circulation for long periods of time after intravenous administration.

Tunable imaging agents

The emission wavelength of quantum dots can be modulated by changing their size.

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Schroeder, A., Heller, D., Winslow, M. et al. Treating metastatic cancer with nanotechnology. Nat Rev Cancer 12, 39–50 (2012). https://doi.org/10.1038/nrc3180

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