A Nanodrug for the Cure of Metastatic Breast Cancer
Abstract
Metastases, including to the lungs and liver, are responsible for approximately 90% of the 40,500 breast cancer deaths every year in the USA. Current therapies for metastatic tumors are tragically insufficient, as ?resistance? invariably sets in, leading to relapse and death, often after a period of success in controlling metastatic spread. Chemotherapy and molecularly targeted therapeutics can be highly toxic, resulting in dramatically reduced quality of life. Immunotherapy is promising for several cancer types, but unfortunately not yet for the vast majority of breast cancer cases. The situation is even worse for triple-negative breast cancer (TNBC), since no targeted therapies are available and treatment options are limited to conventional chemotherapy. We have explored the largely understudied perspective that ?therapeutic resistance? emerges mainly because the biological barriers (circulation, tumor microenvironment, cells, organelles) in the body evolve along with tumor growth and metastasis. These barriers are also present in health and are essentially responsible for ?directing traffic? of cells, molecules, nutrients, and metabolites in the body. At the onset of cancer, the barriers may still behave very similarly to healthy processes, but as the cancer evolves (due to genetic instability), the barriers themselves also evolve, leading to different levels of access or trafficking of substances (drugs, cells) in the body and the tumor microenvironment. Once cancer changes, the characteristics of these barriers, chemotherapeutics, for example, lose their power to combat cancer because they are essentially diverted from their normal transport pathways and end up in insufficient concentration at diseased sites. This is especially true in cancer tissues that have suffered several mutations, which present a large variety of different ?mass transport phenotypes? or what we refer to as a set of characteristics describing the movement or accessibility (penetration) of drugs and cells in the body. For nearly 15 years, we have been developing the basic scientific framework for the above-described view of cancer, termed ?transport oncophysics,? by combining the strengths of molecular and cell biology with physics, engineering, and advanced mathematical models. At the same time, we also advanced approaches to penetrate across the cancer-associated biological barriers and found that the synthetic, innocuous, and biodegradable porous silicon nanoparticles and microparticles are especially effective in this regard. In the last 5 years, partly supported by the Department of Defense Breast Cancer Innovator (Ferrari) and Innovator Expansion (Ferrari, Chang, Shen) Awards, we discovered that drug-loaded nanoparticles, though they do provide modest survival benefits, are unable to completely eliminate metastatic disease, similar to conventional approaches of chemotherapy and molecularly targeted therapies. This forced us to think further out of the box, which led to our recently published discovery (Nature Biotechnology, March 2016) that it is possible to achieve long-term cures (human equivalent of 20+ years, disease-free) for TNBC with lung and liver metastases in about 50% of the cases in preclinical models. At the same time, the overall survival benefit, even for the animals that were not cured, is also unprecedented. We achieved these results with a new, multi-component drug, named iNPG-pDox (injectable nanoparticle generator with polymeric doxorubicin conjugate). This drug is designed so that its components act in a prescribed time sequence to overcome the various metastasis-associated biological barriers and to preferentially deliver the killing principal to the ?heart? (the nucleus, technically) of cancer cells. The key finding for this drug is the recognition that Dox-containing nanoparticles needed to get inside the cancer microenvironment; it is not sufficient to inject them systemically. Using a literary analo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710390
Entities
People
- Jenny Chang
Organizations
- Houston Methodist Research Institute
- United States Army