Paclitaxel in exosomes---50 times less chemo needed

The last quote is interesting: "We don't know exactly how they do it, but the exosomes swarm the cancer cells".
Isn't "delivery" one of the biggest challenges in treatment?
With chemo (which I have limited knowledge of), how do they prevent delivery to good cells to minimize toxicity?

Seems promising. I didn't see any mention of clinical trials, which would be needed.

It would be interesting to see if other anti-cancer compounds could be packaged into these "exosomes" and delivered effectively.

I'm unfamiliar with "liposomal delivery system" as well as "SSDD".
A quick google search revealed research dating back 10+ years of "Liposomal Delivery System" (LDS) protocols, so leggo brings up a good point. How is this different? Further, how effective has the LDS been in the clinic? Perhaps this "exosomes" technique improves on any inefficiencies of "LDS"?

I'd be curious to know the differences.

Unless someone else wants to, I'll email the lead researcher.

Also, and I could very well be wrong, I think anything "somal" is delivered that way with the intent of keeping it in the body longer. That also makes me question why. So the poison is staying in you longer. I'm not so sure that's a good thing....longer in the body, more damage caused. I guess I'm rationalizing but what good is it if it shrinks/kills tumors, but kills me in the process? Guess I'll find out when I start reading about these new exosome thingies.

John asked: With chemo (which I have limited knowledge of), how do they prevent delivery to good cells to minimize toxicity?

Traditional small molecule chemotherapeutic agents cause cell death (cytotoxicity) either directly or indirectly. Unmodified, they are not considered to be targeted agents and are indeed taken up by normal cells. However, they have mechanisms of action which are chosen to selectively kill rapidly dividing cells. Different agents have different mechanisms of action (e.g., platinum agents, alkylating agents, other inhibitors of DNA synthesis or repair; anti-microtubule agents/ mitotic inhibitors that inhibit the mechanism that divides chromosomes into daughter cells). Unfortunately, these are functions of normal cells as well, so they can still impact normal cells (hence the side effects). That said, if a drug candidate is seen to accumulate in non-target tissues with detrimental effect in the development phase, it is discarded.

In contrast, antibody therapeutics are a type of "targeted agent" (e.g., trastuzumab/Herceptin). Due to their antibody structure, they can bind tightly and specifically to their target "antigen" (e.g., HER2). Due to their specificity, they do not bind to other molecules much. Ideally, a targeted antibody therapeutic for breast cancer binds to a target antigen that (1) is over-expressed on breast cancer cells (e.g., HER2 in HER2+ disease), and (2) is not expressed on very many other types of cells (e.g., HER2).

Traditional small molecule chemotherapeutic agents can be modified so that they can be targeted specifically to tumor cells, and not normal cells (e.g., by linking a small molecule to an antibody).

"Targeting" is one goal of "drug delivery", but drug delivery is a very broad area that addresses a variety of problems as explained here. As Leggo notes, it appears that liposomes are not truly "targeted" unless they are designed to incorporate a targeting modality. An example would be immunoliposomes, "in which [antibody] fragments are conjugated to liposomes, represent a strategy for molecularly targeted drug delivery.[9] Anti-HER2 immunoliposomes have been developed with either Fab' or scFv [antibody] fragments linked to long-circulating liposomes."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC346515...

BarredOwl

Email response from the lead researcher:

1. How is your technique different than "Liposomal Delivery System" (LDS) methods?
> There is a big difference between liposomal and exosome-based drug formulations. First, exosomes consist of real cellular membranes, because they are produced by the cells, so they can easily fuse with cancer cellular membranes, and deliver toxic drugs to kill cancer cells. Second, exosomes surface filled with sticky proteins that allow them to adhere and penetrate to cancer cells better. These mechanisms are all part of natural functions of exosomes that play an important roll in delivery of different substances from cell-to cell. So, we utilize just what Nature created to deliver drugs to cancer cells. Finally, exosomes released from white blood cells are a part of immune system of the paint, so they are invisible for their own immune cells, and can circulate in the blood for a long time and find their target. Even more, we found that they know their target - cancer cells, and exclusively deliver the toxic drugs to them, but not to the healthy cells. This way, we can increase efficacy of the treatment, and decrease side effects.

2. Since "delivery" is one of the biggest challenges in treatment, how do you prevent delivery to good cells to minimize toxicity?
> This is still in our investigations. We found out that exosomes released from immune cells have a specific groups on their surface that target cancer cells and tissues with inflammation. It is also the part of the natural mechanism, so we only use what already was created.

3. When is the soonest clinical trials start?
> We are only in pre-clinical investigations dealing with animals. To receive a permission for clinical trials, we need to demonstrate safety, reproducibility, stability and purity our formulation. We are trying to rase money for these investigations right now.

I've been reading about this exosome stuff for the last couple of days, and to be honest, I'm still not seeing the difference. I'm going to ask at my next appointment. Maybe I've become "dense" in my old age, so I think I'm just going to let an oncologist simplify it for me. It'd be nice to here that this is something to look forward to. We'll see.

Thanks for explaining BarredOwl. I'm not so sure though, that the lipisomes used in cancer therapy are synthetic. My understanding is that a lipid is picked off the cell membrane and then manipulated using totally organic molecules (just like exosomes? still unclear to me) to target the specific cancer " cell type", ie: various breast, prostate, lung, etc. I think it's been long known that some sort of package (all this "somal" stuff) has to "hold" the drug until it can be dispersed in the plasma. The part that I was stoked about when it came to lipisomes and that Myocet junk I was given, was that it wouldn't cause an immuno response. That's what scares me about these exosomes. Exosomes sound like they're going to "hang out" with the hopes of creating that immune response. Other than that, they sound identical to me. Exosomes actually sound like a step backwards to me. Perhaps it's just me, but having suffered with an absolutely horrific auto-immune response, I can't even imagine that these exosomes would be better, and in fact, may be worse. Guess I'll find out more next week when I speak to an onc who can simplify it for me. Thanks again for trying to explain the difference to me.....I do think I get it (wiki diagrams helped too), but I'm still not excited that this is something new. Maybe slightly improved......maybe, but not to someone who thinks you shouldn't mess with a perfectly fine immune system. I'm laying my bets on fixing my mitochondria, but that's a whole other story . But hey, whatever works will be a good thing. Maybe exosome wrapped chemo is it. If only they could take chemo out of that equation, I'd be a much happier camper.

Ugh. I'm gonna have to start over so my onc doesn't think I'm a loon when I bring this up. I was pretty sure that the point (kinda) of these exosomes was to trigger the immune system, in addition to getting the chemo to its target. I was positive I read that somewhere. You read it won't, right?

Hi Leggo:

This article originally posted above by Fallleaves discusses some additional effects mediated by exosomes as observed in animal and in vitro studies:

"Exosomes are nanovesicles released from many cell types, but are secreted in substantially higher concentrations from cancer cells."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC403441...

I skimmed it, but it appears exosomes that they can both inhibit and promote certain immune functions. It seems like "tumor-derived" exosomes can inhibit anti-tumor responses:

"At this stage, the contribution of exosomes to tumorigenesis primarily from two complementary processes; the modulation and restructuring of the cellular microenvironment to generate the metastatic niche (9, 10), combined with the attenuation/modulation of tumor immune responses (11, 12). In these cases, exosomes from a range of cells, induce microenvironmental changes in tissue that facilitate tumor formation, while simultaneously disarming anti-tumor immune responses, allowing cancerous cells to migrate, avoid immune detection, attach to secondary sites within the patient, and establish metastatic growth . . ."

"Exosomes possess the ability to disable the cytotoxic arm of immune response by inducing apoptosis in cytotoxic T-cells and reducing proliferation of Natural Killer (NK) cells . . "

That is not a good thing, but it relates to "tumor-derived" exosomes, which have similar bags of tricks to tumors.

In contrast, some exosomes derived from white blood cells like NK cells ("Natural Killer cells") can have some inhibitory effects on tumor growth:

"Exosomes have also been shown to generate anti-tumor immune responses. NK cells release exosomes containing perforin and CD56, as well as granzyme B that have been shown to inhibit tumor growth (58, 59). Due to the contradictory tumor-promoting and anti-tumor responses more research is required to determine if exosome stimulation skews the balance toward a tumor immune escape mechanism."

Seems like they have a long way to go to the clinic.

BarredOwl