Tuesday, August 14, 2012

Nanoparticles: The Basis for a New Hope in Cancer Treatment?

Nanoparticles are extremely tiny particles. To give a comparison, the thinnest human hair has a width of about 0.2 mm or 0.0002 m.  The largest nanoparticles range up to 300 nm or 0.00000003 m in diameter.Why are they of interest? Because new research in the field of what's being called "nanomedicine" disclose these particles are just the right size to pass through the gaps in the blood vessels that feed cancer tumors - while not significantly penetrating healthy tissue.

Hence, a nanoparticle mounted with a chemotherapy drug could feasibly target a cancerous tumor more directly, delivering the drugs to only tumor cells without damaging healthy tissues. As we know, a key problem with all chemo is that it destroys healthy tissue as well as tumor, hence creates lots of collateral damage.

This news is of interest to all those who may face cancer treatments, for whatever cancers they may have - but especially those that require chemotherapy to control. (In my own case, with prostate cancer, I would still likely choose HDR "temporary" monotherapy as opposed to any injection of nanoparticles, but I will get to the reasons for that in a bit).

As the oncologists will tell you, if you are a cancer patient and assuming you really want to know, the growth of new blood vessels is one of the hallmarks of cancer. Thense "angiogenic" vessels are what feed nutrients to the tumors and keep them growing. In terms of nanomedicine, the favorable aspect to this is because of the blood vessels rapid growth they tend to be "leaky" with lots of large gaps in their walls - hence can admit nanoparticles of the right size. In the case of the angiogenic vessels the gaps in their walls can vary from 3nm to 300 nm in size.

Meanwhile the pores in normal human blood vessels runs from 2 - 6 nm in size (again 1nm = 10-9  m) so that nanoparticles of 10 nm - 200 nm are the right size to pass through tumor blood vessels without interfering with or transiting normal vessels.  For this same reason, we expect nanoparticles not to adversely effect healthy tissue.

It's important to realize that not all cancer tumors are built the same, however, so are not all equally susceptible to standard treatments. All cancer cells are surrounded by a kind of protective shell the tumor builds around itself. This tough shell- called a tumor "stroma" -  is hard to penetrate and includes fibroblasts, endotheilial cells, vascular perictyes, and even white cells (immune cells). More inaccessible tumors also have a dense extracellular matrix of interconnected collagen fibers.

In the case of some cancers, such as pancreatic, the stroma is unusually tough and resistant and hence almost entirely impenetrable by drugs. That's why victims of pancreatic cancer seldom live more than a few months to a year. There's virtually nothing in the standard battery of teatements that can help them. However, it is possible that the emerging nanomedicine may come up with nanoparticles that can do the trick by virtue of the EPR (enhance permeability and retention) effect if they can transit the vessels feeding the pancreatic tumors and deliver their chemical loads.

In lab mice, injected with iron oxide nanoparticles (iron oxide is the compound that confers the rusty color to the Martian landscape) micrographs show the entire tumor becomes darker with time - indicating nanoparticle accumulation via the "EPR effect". The downside is the nanoparticles can appear to the immune system to look a lot like viruses and hence trigger an immune response (i.e.g being rapidly gobbled by white blood cells, or phagocytes).

This is an area which definitely merits much more research. Another is finding a way to overcome the "pressure problems" presented by tumors. There is typically high fluid pressure at the center of tumor cores, while in healthy tissues fluid intake and outflow is continually balanced by the body's lymphatic system (which returns excess fluid to the blood stream).  Hard stroma tumors (like pancreatic and aggressive liver, breast) lack an effective lymphatic drainage system so pressure buildup results, with the pressure much higher at the tumor center than periphery.

The bigger the tumor the larger the pressure difference, or what we may call  the "pressure gradient". On account of this high gradient (inhibiting fluid flow everywhere except at the periphery) the primary mode of transport within tumors is diffusion, i.e. the movement of usually particulate mass concentrations from higher to lower pressure regions.  Since of course any nanoparticle are coming from without, they will encounter then the highest pressure barriers at the boundary of the tumor, so are limited in mobility.

This is also an area for further study.

Current Nanoparticles for therapy:

One nanotech medium reformulated for chemo and approved by the FDA is called Abraxane. This is actually based on a nanoparticle made up of the blood protein called albumin, which is then used to encapsulate the chemo-agent known as paclitaxel. (By itself paclitaxel is poorly soluble in water).  A non-nanotech agent used for the same type of target cancers is Taxol, but Abraxane is both more effective and less toxic.

Another currently approved nanotech find is Doxil, which is really a "nano-scale" liposome (fat cell particle) of the usual chemo drug, doxorubicin. The latter has been found toxic to heart tissues, but its nano-form distributes differently so that less reaches the heart. However, on the downside, more is liable to reach the skin where it can trigger "ulcerations".

However, the feeling by many researchers is that some minor skin ulcerations - which can be dealt with by appropriate antibiotic or other topicals - are preferable to cardiac toxicity leading to heart attacks. In the same way, many who choose radiation therapy - such as I am doing - figure that some skin or other minor bladder, rectal irritation, is preferable to having your entire prostate and attendant nerves, blood vessels, "gutted" leaving you laid up in recovery for months. With cancer, it's a case of  "pick your poison" when it comes to treatment and one always hopes to choose that which will preserve the best life quality.

Needless to say, though many more anti-cancer nano-agents are in development, a lot more needs to be done especially to make the cost (currently the average per dose costs of both Abraxane and Doxil are $5,000 each) worth their effects. In the case of the latter, "they offer only modest improvements in overall survival" (e.g. Physics Today, August, p. 41).

Beyond this, the ability to do large scale manufacturing with high levels of standards and confidence is still in the future. As the above cited Physics Today article notes: "Though many labs can make nanomedicines at the milligram level for proof-of-concept in in vitro studies, the costs and manufacturing challenges associated with making large scale batches of the same quality remain great".

So, until the quality control problems are resolved, it looks as though surgery, chemo and radiation will remain the primary modes of cancer treatment - at least for the forseeable future!

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