I am trying to induce the release of a drug from my formulation (polymer+magnetic nanoparticles+drug) using externally applied alternating magnetic field. At my University we have an induction heater (IHG04AC Induction heater, Across International, US) and I tried to use it applying the following parameters:
1. Freq = 250 KHz (Maximum)
2. AC current = 400 A (Maximum)
3. Duration = 9.9 sec (Heating timer range) + 9.9 sec (Dwelling timer range) + 9.9 sec (Cooling timer range)
4. Loops = 3-turns coil with internal diameter of 2.5 cm.
5. Power = 4 KW.
But unfortunately after 10 min with 19.8 s on (since magnetic field is on only in the heating and dwelling time ranges) and 2 min off nothing was released. Even when I used tubes rather than a dialysis membrane to overcome the diffusion limitation and withdrew a sample and centrifuged it to determine the concentration of drug in the supernatant to compare it with a tube that has not been subjected to alternating magnetic field. The concentration of drug obtained from both samples were the same indicating that the magnetic field did not induce any change.
The properties of my formulation includes the following:
1. Ms = 48.6 emu/g
2. Coercivity = 9.85 G
3. Remanence = 0.498 emu/g
4. Concentration in the testing vial = 0.5 mg in 1 ml DI H2O
5. Size of the Magnetic nanoparticles = 5 nm.
So I was wondering what could be the reason for the lack of drug release? Is it the duration of magnetic field applied? or Should I increase the concentration of the magnetic nanoparticles? Or could be it be something wrong with the induction heater itself? Am I using the wrong type of induction heater according to its properties to induce drug release from my formulation?
An advice is highly appreciated if possible to help me in completing this part of my thesis.
Thanks a lot for your help and consideration.
Dear Yasmine,
I'm not an expert but:
We are talking about heat induced drug release, no? If no, no need to read further (c:
Did you chose polymer well?
Are you sure your particles are heating at all? Could you try to measure temperature change of more concentrated samples? Just to see whether there is any heating. If your particles are homemade, there are various parameters that can hinder heating.
I don't think the problem is in the heater. I don't know what settings did you use, but with 400A it creates around 300G inside the coil. 250kHz and 300G should be more than sufficient for heating ferrofluids. I think that periodic 20 second heating is enough if your particles are good. But, why trust me. If you can, try with longer heating time. Especially if you don't know what to expect from your particles.
Regards
not being an expert neither, I'd like to ask simple questions before trying to answer any. This is, becaus I do not thaink that there is a straightforward answer to your query based on the information you provided.
Do I understand right that the polymer is forming some kind of vesicle, ane insider the vesicles there are magnetic particles and drug molecules?
If yes, do you know how many particles you have per vesicle and what the average volumeper vesicle is?
I would think that these parameters shall determine (besides heat loss through the vesicle membrane) the temperature evolution ov the vesicle and ultimately determine whethe it remains stable (closed, no release of drug) or not [in case release is thermal, as Marko suggests].
On the magnetic side, you mention saturation and remnant magnetization, as well as the coercive field. Do you know the conditions under which these were determined and whether their physical origin is understood? It will be particularly important to know and understand whether these quantities have any relationship to the situation in which you try to achieve drug release.
Dear Marko,
Yes I am talking about heat-induced drug release and I have a chosen a polymer that will degrade upon heat application or even at the movement of magnetic nanoparticles within them. And to ensure that heat release was not hindered by the polymer I placed Magnetic nanoparticles alone in De-ionized water of concentration 8 times higher than that I use in my formulation and still no temperature rise was observed. As for using longer time I am actually using the maximum time of the device to apply magnetic field. Another question came to my mind now, Would the crystallinity of my particles be a factor? Should they be highly crystalline to induce heat upon alternating magnetic field application?
Thanks a lot of your help and consideration.
Dear Kai,
Yes, my polymer is forming a nano-shell encapsulating the magnetic nanoparticles and drug within them. Unfortunately I don't know the amount of magnetic nanoparticles within each vesicle nor the volume. As for the magnetic nanoparticles themselves their properties were determined using VSM (Vibrating Sample Magnetometer) at room temperature applying 20,000 G magnetic field. The magnetic saturation obtained is nearly similar to the values obtained by the articles I have read using alternating magnetic field for hyperthermia and drug release as for the Remanence and Coercive values, mine are lower than those mentioned in the same articles. And for whether their physical origin is understood or not? I really didn't understand this part, can you please explain it for me clearly?
Thanks a lot for your help and consideration.
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Dear Yasmine,
Not being an expert neither, I think the problem maybe is your particles. If the particles temperature didn't increase, it would not release drug. Regarding this parameters you have mentioned, I think maybe you can increase the concentration and the particles's size. According to what i remember, to increase particles temperature in AC magnetic field, the particles with size of 5 nm are too samll. Maybe the size of 20nm will be better. So I suggest you to read some published papers about magnetohyperthermia to find the best suitable particles, including the concentration and size. Please feel free to think about my idea. Good luck!
Dear Yasmine,
Heating of magnetic particles is caused by transfer of energy from the external field to the particles. For this purpose your particles must resonantly respond to the external A.C. magnetic field. This is possible by selecting suitable frequency, size and type of magnetic particles. Superparamagnetic nanomagnetic particles having high pyromagnetic coefficient are considered ideal for this purpose.
Yasmine, I won't be able to check all these papers... For now I'll just try to start reformulating the part of my questions you apparently didn't understand.
You say you have determined Ms, Mr and Hc using a VSM. This is usually a much slower experiment and measurement than the AC field you apply for heating.
My question was: do you understand why, given Ms, Mr and Hc have the values you measure and owing to what physical mechanisms they take on the values you have detemined?
Furtheron: In a full M(H) cycle, we usually say that the area enclosed in the hysteresis loop (plotting M(B)) corresponds to the work irreversibly transferred to heat. Now, if Mr and Hc are smaller, as you say, than in the refeences you had found, then so will probably the work you can transform to heat.
But probably, the M(H) cycle at 250kHz (if you could measure it) will not look the same as the (slow) VSM cycle. So the transfer of reasoning is not 1:1.
As to Rasbindu Mehta's resonance, I don't know what kind of resonance you are referring to. Would you mind explaining? FMR or the like is certainly way up in frequency...
Apropos to Kai Fauth answer
I was referring to the case when nanosized magnetic particles are encapsulated and fictionalized with a drug is required to be heated by applying a.c. magnetic field.
Magnetic particles can be heated by two processes. In one ferromagnetic particles are subjected to an a.c. magnetic field. Here heating occurs due to hysteresis loss. The shape of hysteresis curve depends on size of the particles . For larger that is mufti-domain particles it is narrow hence requires less energy for domain wall to move than that for single domain particles which has a broad M-H curve. Reducing size further to the order of few nanometers there will not be hysteresis but the shape of M-H curve will be S-shape –similar to that for larger particles. This is superparamagnetic state where the magnetic moment of the particle will fluctuate in response of thermal energy while individual atomic moment will maintain their orderly state with respect to one another. Relaxation time for net magnetization also called Neel relaxation time . This depends on the ratio of energy barrier ∆E and thermal energy k T.
For ferromagnetic materials with large size energy will be required to overcome barrier to domain wall motion ( which depends on intrinsic anisotropy, impurities and grain boundary in the materials. This energy is supplied by the external a.c. field and there will be continuous flow of energy from the field to the particles resulting into heating the particles. This is the one you have referred.
In case of superparamagnetic particles energy is required to align the particles’ moment coherently to reach to the saturation state. Physics of heating by SPM particles in the a.c. field is described by Rosensweig ( JMMM-252(2002)370 ). In short, the amount of heat generated per unit volume is given by
Pspm= µ0πfχ’’ H2
χ’’ is the imaginary part of complex magnetic susceptibility and depends on frequency. Hence driving frequency should match so as to have maximum χ’’ (Fannin P C, Scaife B K P and Charles S W, JMMM,122(1993)159). It is also known that SAR is significantly larger for SPM particles (Hergt R, et al , IEEE Trans. Magn. 34(1998)3745).
Hence for better heat generation either ferrofluid ( in which nanomagnetic particle exhibits extrinsic super paramagnetism) or intrinsic SPM should be preferable.
Rasbindu, thanks for the explanation(s). Sounds fine to me. But in what you describe I have not identified any mechanism which would qualify as a resonance phenomenon to me (correct me if I'm wrong). And I wouldn't have expected one to be there and was surprised to read it in your first post.
But then, maybe what you refer to as matching the driving frquency for largest χ’’ is what I would call tuning the frequency to a resonance? And is SAR the acronyum for the resonance phenomenon? I don't know what SAR is, could you briefly explain?
To my knowledge, in addition to Néel relaxation there is also relaxation by rotation of the particles in liquid environment (is that Brownian relaxation?). I am not sure whether it plays a significant role in this size and frequency regime.
Otherwise, of course the situation you were referring to (drug is present at the particle surface) is quite different from what Yasmine is trying to achieve (drug is present in the same 'container' as the particles). In the former case the heat released (by whatever mechanism) is created exactly where the drug is 'waiting for it' while in her case it is necessary to heat the entire volume.
Yasmine, I guess it will be useful to make some order of mgnitude estimations on how much energy per vesicle shall be necessary to generate the thermal energy required. And do ot ferget that there will be heat loss across the membrane to the outer world.
Thank you very much Kai. I was referring to your question ' I don't know what kind of resonance you are referring to. Would you mind explaining? FMR or the like is certainly way up in frequency...'. Yes, driving frequency should match with the frequency at which χ’’ is maximum.SAR is specific absorption rate and is a Specific absorption rate (SAR) and is a measure of the rate at which energy is absorbed by the human body when exposed to a radio frequency (RF) electromagnetic field. Yes, when the medium is in fluid state there will be also Brownian relaxation and this may result in what is referred as extrinsic superparamagnetism. For the polymer+magnetic nanoparticles+drug this extrinsic superparamagnetic behavior is useful for heating of the particles for hypermedia (pl. refer Zong answer above) and may be drug release. For the later thermoresponsive polymer is preferable. For this aspect we have made some preliminary research using static magnetic field.( "Biodegradable thermoresponsive polymeric magnetic nanoparticles: a new drug delivery platform for doxorubicin" J. Nanoparticles Research,DOI 10.1007/s11051-010-9921-6, (2010)
4 days ago
Dear Kai & Rasbindu,
Thanks a lot for your advices. I will take them all into consideration. Hope I'll be able to achieve my target.
Thanks again for your help and consideration.
Dear Yasmine,
as others have mentioned unless the nanoparticle is heating at the specific frequency (and magnetic field strength) you are using you will not see drug released. I am assuming that the hydrodynamic size of your particles is larger than 5nm but particles at that size have been shown to heat with the right frequency and field strength.
One of the many limitations of basic induction heaters for this application is the severe limitation on frequencies that can be applied - if you can only attempt to heat at 250 kHz you are not seeing a full frequency response profile for your particles - this is why we developed the magneTherm system for this application with a range from 50 kHz to 1 MHz at variable field strengths up to 25 mT - details at www.nanotherics.com.
Regards
Carl
Dear Dr. Carl,
How would I know the appropriate frequency and magnetic field to be applied on my Magnetic Nanoparticles to ensure drug release from my formulation?
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