Having a specific nanosize or functionality alone is not enough to guarantee good drug delivery to target tumours
The complex microenvironment of tumours is presenting a challenge in developing effective anticancer treatments that attempt to harness nanotechnology. (Purdue University image/Bumsoo Han, Kinam Park, Murray Korc). Credit: Purdue University
Researchers in the US involved in a national effort to develop cancer treatments that harness nanotechnology are recommending changes in the field because experiments with laboratory animals and efforts based on current assumptions about drug delivery have largely failed to translate into successful clinical results.
This assessment was advanced in an article by Bumsoo Han, a Purdue University associate professor of mechanical and biomedical engineering, Kinam Park, a professor of pharmaceutics and Purdue's Showalter Distinguished Professor of Biomedical Engineering, and Murray Korc, the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine in the National Cancer Institute's Cancer Nanotechnology Plan 2015, a 10-year roadmap concerning the use of nanotechnology to attack cancer.
Researchers are trying to perfect 'targeted delivery' methods using various agents, including an assortment of tiny nanometre-size structures, to selectively attack tumour tissue. But the current direction of research has brought only limited progress, say the authors of the article.
We should realise that having a specific nanosize or functionality alone is not enough to guarantee good drug delivery to target tumours
One approach pursued by researchers has been to design nanoparticles small enough to pass through pores in blood vessels surrounding tumours but too large to pass though the pores of vessels in healthy tissue. The endothelial cells that make up healthy blood vessels are well organised with tight junctions between them. However, the endothelial cells in blood vessels around tumours are irregular and misshapen, with loose gaps between the cells.
'We should realise that having a specific nanosize or functionality alone is not enough to guarantee good drug delivery to target tumours,' said Park. 'The tumour microenvironment is just too complex to overcome using this strategy alone.'
The authors point out that research with laboratory mice has rarely translated into successful clinical results in humans, suggesting that a more effective approach might be to concentrate on using in vitro experiments that mimic human physiology. One new system under development, called a tumour-microenvironment-on-chip (T-MOC) device, could allow researchers to study the complex environment surrounding tumours and the barriers that prevent the targeted delivery of therapeutic agents, they say.
The approach could help drugmakers solve a major obstacle: even if drugs are delivered to areas near the target tumour cells, the treatment is still hindered by the complex microenvironment of tumours.
'We used to think that if we just killed the tumour cell it would cure the cancer, but now we know it's not just the cancer cells alone that we have to deal with,' Korc said.
An 'extracellular matrix' near tumours includes dense collagen bundles and a variety of enzymes, growth factors and cells. For example, surrounding pancreatic tumours is a 'stromal compartment' containing a mixture of cells called stromal cells, activated cancer-associated fibroblasts and inflammatory immune cells.
In addition, hyaluronic acid in this stromal layer increases the toughness of tumour microenvironment tissue, making it difficult for nanoparticles and drugs to penetrate.
Another challenge is to develop water-soluble drugs to effectively deliver medicines.
'Recent advances in tissue engineering and microfluidic technologies present an opportunity to realise in vitro platforms as alternatives to animal testing,' Park said. 'Tumour cells can be grown in 3D matrices with other relevant stromal cells to more closely mirror the complexity of solid tumours in patients. The current ability of forming 3D-perfused tumour tissue needs to be advanced further to create an accurate tumour microenvironment.'
Such a major shift in research focus could play a role in developing personalised medicine, or precision medicine, tailored to a particular type of cancer and specific patients. More effective treatment might require various 'priming agents' in combination with several drugs to be administered simultaneously or sequentially.