You have many options. I'm interested in camptothecin (camptothecin, topotecan, gimatecan, belotecan, lurtotecan, ect) and indenoisoquinoline structures (indotecan, imiditecan, MJ-III-65,etc), which have been proven to be very good antitumoral and antileishmanial activities. The main advantage of these compounds is their well defined mechanism of action.

http://www.ncbi.nlm.nih.gov/pubmed/19383846

http://www.ncbi.nlm.nih.gov/pubmed/22850521

http://www.ncbi.nlm.nih.gov/pubmed/23611704

Among these compounds there are many promissing structures whose toxicity make them no useful in human cancer treatments. Maybe this could be a good start point.

You have many options. I'm interested in camptothecin (camptothecin, topotecan, gimatecan, belotecan, lurtotecan, ect) and indenoisoquinoline structures (indotecan, imiditecan, MJ-III-65,etc), which have been proven to be very good antitumoral and antileishmanial activities. The main advantage of these compounds is their well defined mechanism of action.

http://www.ncbi.nlm.nih.gov/pubmed/19383846

http://www.ncbi.nlm.nih.gov/pubmed/22850521

http://www.ncbi.nlm.nih.gov/pubmed/23611704

Among these compounds there are many promissing structures whose toxicity make them no useful in human cancer treatments. Maybe this could be a good start point.

Hi,

sounds nice. How about some microRNAs. I know some that might work well for certain cancers. I could eventually provide a test system...

Best...

Peter

Hi,

It sound nice ... how about the stage of cancer. I mean the possibility of applying it in early or late stage of cancer without resistance.? because some of cancer drugs are encounter with strongly resistance done by cancer cells?

There are multiple types of cancer resistance for certain drugs, and drug resistance is easier developed for some drugs and by particular types of cancer. For example resistance against Doxorubicine can either be caused by the presence of ABC transporters pumping drug molecules out or by over expression of DNA repair enzymes. Nanoparticles can help in fighting drug resistance by releasing multiple drugs simultaneously, or drug together with adjuvant, and are generally too big to be pumped out by ABC pump.

Thank you for your explain. just one things is there any limitation or restricted for releasing multiple drugs via this Nanoparticles. For instance, in breast cancer drug resistance is different during the degree of EMT ( Epithelial or Mesenchymal stage ).

Thank you.

One can encapsulate various drugs / adjuvants, we didn’t check the limit but 3-4 types shouldn’t be a problem, with guarantee of one package delivery. But I don’t know how to release only certain drugs depending on cancer cell cycle. Drugs will be released together. We can only try to target different cells with different types of nanoparticles, or release same load in every cancerous cell.

You need to test the molecular mechanisms of cell death induced by these drugs. Maybe they have non-specific targets inside the cells.

Yes, you can use nanoparticles to decrease side effects of those drugs. Better, if these particles have functional groups: i.e. with RGD, folate or antibodies.

You can also entrap any drug on the nanoparticle. You can try new molecules, including siRNA or microRNA-based molecules (miRNA inhibitors or miRNA mimics).

What are your thoughts on mylotarg - drug conjugate used in AML. Now no longer available in usa

Good idea, we can try with Calicheamicin or Esperamicin. They are very potent drugs and are also very toxic. Do we also need antibody targeting CD33?

Hi Tomasz,

Good question! I guess any hydrogen peroxide-generating approach could be a good idea to kill the cancer cells, sparing the normal ones! Also, TRAIL-targeting approaches could be tried!. But personally i do not trust the targeted treatments as there are more than possible targets in the cancer cells. Targeting only one molecule could only result in kill some fraction of whole cell population, which eventually result in the increase in the resistant clones that must be responsible for the failure of treatment in long term. Good luck! ([email protected])

Cancer

http://link.springer.com/article/10.1134/S0022093013020175

Hello Tomasz,

I suppose that effective result may be reached with formation of inclusion complex, such a b-cyclodextrin or its derivatives like a hydroxyethyl-bCD or hydroxypropyl-bCD or some othes.

Currently many kinds of NPs have been mainly applied to improve drug absorption, delivery and bioavailability. It is indeed a good idea to use NPs to reduce the side effects. However, the potential toxicity or unknown hazards of nanomaterials itself remains to be fully elucidated. The following might be helpful:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527668/

Examine the pharmacokinetics of drugs under consideration. Only drugs that remain at the site of required action after being delivered there would benefit. If they do not, then the drug pharmacological concentration will not be reached and hence there will not be any significant activity. Also, consider what are the sites of toxicity of each drug. If the carrier/nanoparticle also increases delivery of the drug to the site of toxicity than the toxicity versus benefit ration will not be improved.

Nanoparticles can be toxic, that’s why I try to use biodegradable ones. We make NP from polysaccharides – dextrane, starch, hyaluronan. I also think that simple targeting will not help, like single drug that stops only one path. That’s why we want to put multiple drugs, and multiple targeting molecules. We also hope that polysaccharide NP will be “attractive” due to Warburg effect.

I am afraid, that RGD is too popular, every cell will be targeted. I will read the text.

Instead of selecting one substance to be universal for all kinds of tumors I would rather opt for two scenarios: 1. find most commonly upregulated pathways in certain cancer and identify substances that interfere with it and than try to encapsulate and deliver. I think that many drugs that are causing to much collateral damage when given systemic and fail phaseI/II studies could be delivered to a cancer cell taht way producing good results. 2. make a 'coctail' of drugs. Good luck!

And a cocktail of side-effects, no doubt.

You all should try to understand that the pharmacokinetic properties that allow a drug to be active (both therapeutically effective and toxic) after SYSTEMIC administration make the drug unsuitable for site-targeted delivery!

I guess than some toxicities but not all, can be reduced by carryng drug in Nanoparticles and things alike, it would be of interest knowing the type of drug, what is known about its mechanism of action, the kind of Cell lines on which it has some efficacy, and the nature of toxicity detected, and in what species, probably just as a matter of curiosity, as, if toxicity was detected in non-human tests, even when a toxicity found in an animal species should not mandatorily be present in humans, as animal studies remain the only way available to detect a serious toxicity of a Drug before putting it in phase I, even when phase I trials of anticancer drugs are conducted in Cancer patients willing to accept being included as subjects, a prohibitive toxicity in animal studies would block any further development of drug, and species closer to mankind, as primates, specially chimps, not only are extremely expensive as subjects of experiences, but as the degree of protection it get is growing every day, conducting this type of research in species close to humans is becoming an unsurmontable hurdle. I can hardly imagine a way to solve the problem of a serious toxicy of an anticancer product but a trial and error approach in an affordable animal species with the toxicity's corrective measures considered.

The idea of cancer treatment with multiple drugs (cocktails) came In 70’s, and was inspired by tuberculosis treatment. It is more efficient then single agent therapy because cancer cells evolve and get resistant for single agent, sometimes few weeks from treatment start. Mostly by ABC transporters pumping drug out of the cell, overexpresion of DNA repair enzymes, bypassing of a blocked metabolic path. Don’t forget that many drugs works only if cell is in the specific cell cycle phase. Drug cocktails proved to be more efficient then single agents. As to side effects, when You inject Doxo directly to the blood vessel, it simply dies after few injections, so even simple prolonged release will decrease side effects.

Dear Krzysztof, I don’t even dream about solving all the problems with our polysaccharide nanoparticles. I will be very happy to find efficient application for one type of cancer… I am afraid that we need to apply multiple agents which breaks one metabolic path in two places. And targeting molecule. I desperately look for good ideas to try… And for help of oncologists… I am a simple engineer of molecules…

Dear Tomasz, can you functionalize your nanoparticles with transferrin? take a look this http://scholar.google.com.au/scholarcluster=3233830912816817239&hl=it&as_sdt=0,5&as_vis=1

Dear Orazio, I think I can, it is very easy to form covalent bonding on polysaccharides nanoparticles, but suggested link doesn't work, could You pplease send another or PDF... We were thinking about transfferin receptors.

FWIW, I am ignorant about the difference between the nanoparticle approach you describe vs. targeted antibody-drug conjugate drugs that make sure the extra-toxic payload is delivered to the targeted kind of cells. If a simpler ADC solution suffices, I don't understand the need for a more complicated approach.

Dear Tomasz, in attachment a paper about the functionalization of nanoparticles with transferrin....it looks promising...

Formulation can reduce toxicities in some cases. For example aphotericin B had renal toxicity as a main side effect, dose limiting. By encapsulating in liposomes the dose limit was increased several fold by Nexstar, later licensed to Fujisawa, I believe.

Doxorubicin is studied in this context.

http://www.ncbi.nlm.nih.gov/pubmed/21295088

I think it could be a nice proof of principle to bind DOX with your polysaccharide nanoparticles and test it versus other DOX’es in an established mouse cancer model e.g. T41 – described in the article. Actually we have that model running in our Dept. We are also good analyzing of immune cells that infiltrate the tumor. So we could possibly not only follow tumor growth, survival but also the effect on immune response after different treatments.

how about some radioactive substances, like radioactive iodine as used in thyroid disease? That may allow a useful combination of destruction of the target cells with a manageable risk of acceptable side-effects due to the biological half-time. (this is NOT an expert advice, just consider this as brainstorming starting point). The experts should be found within the the area of radiology.

Cancer

http://link.springer.com/article/10.1134/S0022093013020175

@Viktor Kotolupov

I do not see how your book chapter could help in this question.

targeting cancer cells is challenging as cancer proteins can mask the detection so that is one question in itself. relating to nanoparticles, one project I'm working on is relating to ~ 50nm particle distribution in sample of a gold-bound drug API that is emulsified to give it site recognition affinity imrpovements. the partial lipid composition provides additional targeting capability, but also provides a depo effect in bathing the cells with drug compound. this combined with the technique of metronomic dosing of the cancer drug provides for reduction in SAEs and toxicity of dose and scheduling. metronomic dosing is giving a smaller amount of dose more refrequently than the typical carpet bombing approaches of bolus dosing. there are many papers for each of these areas, but in aggregate, you could have a nice system...

To preclinical test for slide effects it can be useful to check for off-target interactions. This is also important for considering the distribution in the body, since off target interactions even though they are fast occurs frequently and thus decreases the distribution efficiency.

Chech this publications:

Drug Discovery and Development (05/14/2012)

Quartz Crystal Microbalance Technology Provides Biologically Relevant Data

Teodor Aastrup and Ingo Montenbruck

Biosensors and Bioelectronics (2012)(In Press)

A novel approach to determining the affinity of protein–carbohydrate interactions employing adherent cancer cells grown on a biosensor surface

Diluka Peiris, Anatoliy Markiv, G. Paul Curley, Miriam V. Dwek

International Journal of Nanomedicine, 27 Feb. 2012, 2012:7 905–914

Functionalization of single-walled carbon nanotubes and their binding to cancer cells

S.Y. Madani, A. Tan, M. Dwek, A. Seifalian

Hi! Not to be a buzz kill, but I see that your synthesis takes place in water. Several of the good chemotherapeutics are not very soluble in water, so before going on a shopping spree make sure the ones you buy actual dissolve to the degree you need. Also I know some are not stable at alkaline pH. So if you use a pH shift in the binding you should also ensure that the used payload can take this pH shift.

I know these are boring basic comments, which you properly are aware of, it is just so annoying doing all the work and then finding out nothing bound/or was deactivated.

How do you propose to quantitate the payload to your particle? I see a lot of potential pitfalls here.

In the case of completely water insoluble stuff (taxol) we use microfluidic nanopercipitation, works nice, or synthesis in DMSO. But we prefer covalent bonding of the drug, such nanoparticles have much higher stability and offers better control – drug is released inside the targeted cells.