Intratumoural injections

[Tridimity]

Why aren't intratumoural injections of chemotherapeutic agents used routinely in the clinic? There are some issues with diffusion of the drug when administered in this way, however a more targeted approach would prevent the side-effects of systemic administration of chemotherapy by IV injection or by oral administration. I can't seem to find any data on the efficacy of intratumoural versus IV injections of chemotherapy in the literature, although intratumoural injections feature in some in vivo models and clinical trials. Intratumoural injection would allow for the delivery of viruses (1), RNAi (2), miRs (3), radioactive microspheres (4) or classical chemotherapeutic agents targeted against tumours. Another potential advantage is that the drugs could probably be used at higher concentrations than is currently possible with drugs administered systemically.

 

1. Harrington KJ, Vile RG, Melcher A, Chester J & Pandha HS (2010) Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics. Cytokine & Growth Factors Reviews 21 (2-3): 91-98

2. Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G & Sood AK (2011) RNA intereference in the clinic: challenges and future directions. Nature Reviews Cancer 11: 59-67

3. Biagioni F, Ben-Moshe NB, Fontemaggi G, Canu V, Mori F, Antonni B, Di Benedetto A, Santoro R, Germoni S, De Angelis F, Cambria A, Avraham R, Grasso G, Strano S, Muti P, Mottolese M, Yarden Y, Domany E & Blandino G (2012) miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours. EMBO Mol Med 4(11): 1214-1229

4. Morawska ME (2013) Imaging: Radioactive microspheres - see and destroy. Nature Reviews Clinical Oncology 10: 124

 

 

Edited October 4, 2013 by Tridimity

[CharonY]

I think the evaluation of efficacy in clinical settings is still underway, from what I see. There are different approaches with which to control release (using polymers such as PLGA, for example) and preclinical results are promising (as they tend to be). I think there are not enough trials to show overall better performance yet, though there many proof-of principle papers to be found.

There is also a nice review discussing advances and challenges of drug delivery:

Wolinsky et al. 2012 Journal of Controlled Release

Volume 159, Issue 1, 10 April 2012, Pages 14–26

[Tridimity]

Thanks, the Abstract of the review looks interesting, I will read the full text once I regain access. It seems, then, that it is mostly a lack of clinical data that is holding back the development and implementation of this mode of drug delivery. I wonder how easy or difficult it would be to access various tissues in this way and I am surprised that it has taken so long for researchers to begin to investigate methods of local administration of chemotherapeutics in this way - especially for the more accessible cancers, such as certain skin or head and neck cancers.

[CharonY]

Localized treatment has been under investigation for quite a long while, but it really depends on the type of cancer and the localization, obviously. There are quite a number of issues, including that in some cases there were no benefits found over systemic approaches (as in the case of gliomas, if memory serves). One issue is that in order to really benefit from it one would need to deposit a high concentration of the substance but let it diffuse to the tumor cells over time. This is what triggered the interest in using polymers for drug delivery and release.

 

For skin cancer there are actually topical treatments using 5-fluorouracil application directly to the skin, for example. Also I would assume that easily accessible tissues areas would often be removed surgically.

 

In addition there are also some commercially available drug delivery systems for the continuous release of therapeutics, though not as a local cytoxic (goserelin comes to mind). That being said, a quick check of clinical trials in the US indicated that quite a few trials have started around 2000 and those not terminated have finished between 2007-12. Of course these vast majority are propriety systems so they generally do not post the results publicly. I.e. there is definite interest to create local delivery systems, for a variety of cancer targets.

[sialic acid]

You still have to show that injection right into the tumor will be better or provide added benefit compared to what can be done surgically or with radiation. Many tumors can be removed with techniques and technology we already have, it's the metastases however that kill you, which of course will be very hard to contain without systemically administering something...

 

 

With regards to drug delivery technology, no one wants to point out the elephant in the room, but one of the biggest hindrances to drug delivery technology is the technology itself. Whenever you package something into a delivery device it is considered to be a new entity by the FDA and all clinical trials must start over from scratch again. Often times, however, delivery devices are developed separately from new small molecules and biologics designed to be new drugs. If I'm a drug manufacturer that just spent $100 million to get my drug through clinical trials to show safety, why would I use a drug delivery device if I had to start all over again from phase I?

 

Many times companies that develop new drugs simply aren't willing to partner with drug delivery technology owned by another company in the early phases of trying to get a new drug approved either. IP and regulatory roadblocks are a major major problem in the realm of drug delivery. Yes you can find a few fleeting examples of drug delivery technology that is being used, but for all of the money we've dumped into it, the returns are quite underwhelming IMO.

 

The #1 way to create a new drug is still to improve the chemical design of your small molecule and give it directly to a patient rather than using some complicated delivery system that is clouded with IP and regulatory issues.

Edited December 1, 2013 by sialic acid