Temperature Sensitive Liposomes in Anti Cancer Therapy

Sponsored Links

Liposomes were discovered in mid 1960s and were depicted as cell membrane models. Deeper understandings, nontoxic nature of these liposomes combined with hyperthermia paved new path for their effective use in Cancer treatments. The drug is placed in the heat/temperature sensitive liposomes and is administered using suitable catheter. When these sensitive liposomes come into contact with tumor cells the phospholipid layers get dissolved and releases the drug in the targeted area.

My presentation includes:
a) Introduction to Liposomes
b) Hyperthermia – role in cancer treatment
c) Formulation of temperature sensitive liposomes
d) Ultrasound Apparatus in Hyperthermia

Keywords: Liposomes, Hyperthermia, Formulation of liposomes, Tomographic ultrasound probe

Profile link of the author: http://www.pharmainfo.net/sirisha
Profile link of the guide: http://www.pharmainfo.net/rojarani

Comments

Virag Shah's picture

Hello madam, Your presentation is novel....its interesting..... As you are detail with temperature sensitive liposomes, the most common methods of preparation of liposomes its self uses high agitation/high propeller which might rise the temperature during formulation. Is this effect the final formulation or is their any special technique to formulate TS-Liposomes.Can you elaborate something ? Regards, Virag Shah http://www.pharmainfo.net/viragshah
Sirisha Pingali's picture

hello virag thank you for the valuable comment I hope i can give you satisfactory answer. Let us see the general method of preparing liposomes. 1. Powdered lipids+ lipid soluble drug are added to organic solvent in RBF 2. It is subjected freeze drying process --> formation of lipid cake 3. Aqueous soln+water soluble drug is added to the lipid cake 4. Hydration and Agitation process 5. Formation of large multilamellar vesicles LMVs 6. LMVs---> Sonication & Homogenization---> formation of small unilamellar vesicles Step 4 may increase the temperature of the formulation as you said. So severe agitation should be prevented. Also the Sonication process causes degradation of lipid core and other soluble ingredients in the formulation. This is now replaced with French press where high pressures are applied. The disadvantage in this is its very costly equipment. When the temperature exceeds 42/46oC or 113oF the lipid core dissolves and releases the drug-->Thermosensitive liposomes. In this case, the process should be selected carefully While for the preparation of normal liposomes other methods can be applied viz. Mechanical agitation Solvent dispersion Detergent solubilization etc Ref.: http://www.authorstream.com/Presentation/vsnmurthy-331492-liposomes-ppt-...

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Abhishek Rathi's picture

Dear Sirisha, Good presentation & topic too. I have a query that during formulation is there any effect of pH along with main factor i.e. Temp as you mentioned? Regards

Abhishek Rathi

Sirisha Pingali's picture

dear abhishek thank you for the valuable comment. Coming to your query the relation between pH and temperature is the same which we study in ceutics. As temperature increases--> viscosity decreases-->mobility of ions increases Other side is increase in temperature -->causes dissociation of ions (especially for weak acids and bases). Since pH is -log[H+], it deviates. So generally when we mention temperature the pH should also be read. for eg. temp 22oC ,2.05 pH. The pH is adjusted using suitable buffers so that it shows minimal deviations when hyperthermia is applied. Ref.: http://www.reagecon.com/techpapers/effectsoftemperatureonphv4.pdf

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Abhishek Rathi's picture

Dear Sirisha, As you mentioned Temp sensitive method, you'll get many references related to pH sensitive methods specifically. So query was raised. Some relevancy in proportion of Temp & pH, individual effect should be also taken in consideration.

Abhishek Rathi

ketanchaudhari's picture

hello madam, your presentation is good but can u reply with more applications other than anticancer therapy of temperature sensitive liposomes

KETAN CHAUDHARI

Sirisha Pingali's picture

ketan thank you for the valuable comment.. Well, Thermosensitve liposomes are used for targeted delivery of chemotherapeutic drugs. The research is mostly carried out in the cancer area because of their systemic action rather than the required local action.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Santosh kumar. JH's picture

Please let me know... What is the difference between Systemic action and Local Action for drug therapy?? Which is ideal for drug targeting?? I think these thermo sensitive liposomes are more used for Local action to selectively target the tumour tissues by using some physical means like ultrasounds etc with an molecular targetting ligands to specifically identify the tumour tissues and release the drug.. Am I right???
Sirisha Pingali's picture

hello santosh.. the latter part of the comment is right. "Systemic" action in my comment means the side effects "affecting the whole system" which is undesirable. "Local" action is the key in cancer therapies.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Santosh kumar. JH's picture

What would be the case if it is leukemia which is dynamic, it can spread systemically ??
Santosh kumar. JH's picture

What would be the case if it is leukemia which is dynamic, it can spread systemically ??
Sirisha Pingali's picture

Well santosh, Metastatic cancers are applied with whole body hyperthermia but owing to its side effects it is not advisable. Moreover this combination treatment is used to treat cancers affecting particular section/region. Ref.: www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Santosh kumar. JH's picture

Hello Sirisha, Nice presentation form you. I certainly had some doubts please clarify me?? 1. Whether the primary purpose of Stealthing a liposome is to avoid the oposination by the phagocytes or to render the liposome to undergo Crystalline Phase transition?? Is their any co-relation between these two physical and physiological mechanism?? 2. Please throw some light on thermodynamics of the hyperthermia in-vivo as a physical phenomenon?? 3. Do you think, this Hypothermia approach will serve the purpose of targeting the tumour tissues?? since we are using temperature as means of targeting ligand like more specifically to increase the EPR ; can it be selectively toxic to tumour cells rather than to normal cells. I dont think so?? Please give your words on this...
G.Sailesh's picture

What is the range of temperature commonly employed in this type of treatment? Why thermosensitive liposomes respond to external stimuli that is to ultrasound and how are they different from normal liposomes? How these thermosensitive liposomes selectively reach the cancer cells?
Sirisha Pingali's picture

hello sailesh thank you for the valuable comment. Coming to your queries The temperature range is usually from 42-46oC or 113oF app Thermosensitive liposomes are designed in such a way that they release the drug upon local heating. Hence the name "thermosensitive". When the temperature crosses the above range the lipid core dissolves-->bursting of the drug Well, these liposomes first reach the systemic circulation. Due to hyperthermia (heating a particular tumor portion) causes increase in the pore size of blood vessels--> permeation of thermosensitive liposomes-->dissolution of lipid core-->preferential targeting Ref.: http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

G.Sailesh's picture

So, you mean to say that the liposome reaches every cell. We have to locate the tumor and apply some kind of external stimuli so that the drug is released only at the tumor. Am I right? Another query is what additional qualification is making this liposomes thermosensitive. In case of magnetic liposomes presence of magnetite material is making it guided by external magnetic field. Then what about your liposomes.
Sirisha Pingali's picture

sailesh.. Thermo sensitive liposomes are formulated using 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG). This lipid is a combination of 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine. Another key ingredient is 1,2 distearoylglycerophosphacholine which increases the circulation of liposomes under hyperthermic conditions. This typical formulation using DPPGOG DSPE etc increases the drug release at the phase transition temperature of liposomes. Ref.: http://www.patentstorm.us/patents/6200598.html http://clincancerres.aacrjournals.org/content/10/6/2168.full.pdf

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

G.Sailesh's picture

Whether this kind of targeting comes under active targeting or passive targeting? Can you please clarify more about stealth liposomes and their function
Sirisha Pingali's picture

hi sailesh, Two types of targeting are achieved in liposomal drugs - passive ligand mediated (active). Coupling of ligands- antibodies to the liposome surface is a good example for active targeting. A brief note on passive targeting and active targeting is given in the following link. I m unable to mention single point because the whole article seems to be interesting. I think it would be fine for you to just have a glance regarding examples and research in the link. Coming to stealth liposomes, they are formed by coating the outer liposome surface with hydrophilic polymers like PEG. The main PK characteristics of SL is 1. decreased rate of clearance 2. dose independant PK --> used in targeting tumors Ref.: http://books.google.co.in/books?id=H3aavfT6oeQC&pg=PA61&lpg=PA61&dq=pass.... The concerned topic can be seen from page 61 of the above link. Thank you

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Santosh kumar. JH's picture

Hyperthermia increases the pore size of blood vessels right?? Why it is needed to increase the pore size of vasculature of tumour cells.. Since there are already fenestrated with pore sizes of 30-80 nm (due to absence of basement membrane between endothelial cells)will this pore size is not enough for maximum EPR effect?? and more over the temperature inside the tumour vessels are more than other normal vessels all these are a part of natural mechanism adopted to feed the rapidly divided tumour tissue. Will this temperature is not enough to melt the lipid core to release the drug ?? I believe the major drawback of cancer therapy is lack of site specificity and drug expulsion by efflux transporters, please clarify how they reach the target tumour site?? and whether these thermo sensitive liposomes can modulates the drug expulsion effect of efflux transporters??
Sirisha Pingali's picture

Well, nm sized particles may cross but micron sized liposomes may not the cross the vessels (LUVs). yeah the temperature inside tumor cells is more comparitively. But that temperature isnt enough to dissolve the lysolipids. So slight raise in temperature is required. Research says hyperthermia treatment may cause shrinkage of cancer cells. Since this area is under study i didnt get much information regarding their effect on efflux transporters and all. If you have got any, i ll be pleased to listen to it. Thank you

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Prof. J. Vijaya Ratna's picture

Sirisha Congratulations for the way you are handling all the difficult questions. Vijaya Ratna
Sirisha Pingali's picture

thank you madam for your encouraging comment

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Anil kumar appapurapu's picture

Abstract: "When these sensitive liposomes come into contact with tumor cells the phospholipid layers get dissolved and releases the drug in the targeted area" pls explain the following Q1) is there any changes in phospholipid layer of tumor cell and normal cell if it is so, Q2) how these liposomes will selectively bind to tumor cell

anilkumar

Sirisha Pingali's picture

hi anil thank you for the valuable comment. the phospholipid layer here indicates the liposomal layers. Liposomes in systemic circulation--> high temperatures at tumor portions--> dissolution of outer layer of liposomes--> availability of drug. You can find furthur information regarding hyperthermia and its applications in the posted references.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

SS Md Shafi's picture

hi... Is there any disadvatages of ultrasound hyperthermia machine..?? what are they..?

shafi ..

Sirisha Pingali's picture

Let us see how the machine works. Due to the application of ultrasound vibrations, the tissue cells move rapidly which results in friction between them causing rise in temperature. Just like rubbing our hands--> mild heat is generated. We can draw general limitations here ~ Skilled personnel is required ~ Excess heat may lead to boils or burns in the area ~ Finally, common to any equipment - its cost.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

SS Md Shafi's picture

hi... how can you prepare liposomes containing doxorubicin..?? , plz... tell me intratumoral distribution of doxorubicin...???

shafi ..

Sirisha Pingali's picture

hello shafi.. thank you for the valuable comment. Preparation of liposomes is done in following steps: 1. Powdered lipids+ lipid soluble drug are added to organic solvent in RBF 2. It is subjected freeze drying process --> formation of lipid cake 3. Aqueous soln+water soluble drug is added to the lipid cake 4. Hydration and Agitation process 5. Formation of large multilamellar vesicles LMVs 6. LMVs---> Sonication & Homogenization---> formation of small unilamellar vesicles Liposomes are phospholipid molecules that are capable of encapsulating active drugs (antibiotics,antineoplastics). Stealth liposomes containing doxorubicin(DOXIL) are done with surface coating of Methoxypolyethyleneglycol (MPEG). Intratumoral distribution of DOXIL: DOXIL - Doxorubicin HCl is an antineoplastic. Features: ~ Has rapid rate of penetration ~ Inhibits mitotic division ~ Has rapid chromatin binding ~ Inhibits nucleic acid synthesis ~ Causes mutagenesis and chromosomal aberrations Main side effect is MYELOSUPPRESSION. Coming to intratumoral distribution, DOXIL is tested in normal and Kaposi sarcoma affected patients. 20 mg/m2 Doxil(r) is injected in both categories. Biopsies were collected from KS and normal lesions at 48 and 96hrs respectively. The concentration of Doxil(r) was found to be more in KS lesions than in normal at 48hrs posttreatment. Thus more drug is delivered to the tumor patients than normal ones. Reference : http://www.kodc.or.kr/cmed/down/DOXIL_PI.pdf

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Sandeep Reddy's picture

hi nice presentation and am appreciating for the answering the difficulty questions 1)can give more applications in the treatment of canser by liposomes? 2)then what kind of materials used forthe preparation of liposomes? 3)weather magnetic liposomes can we use in the treatment of cancer?
Sirisha Pingali's picture

hello sandeep thank you for the valuable comment. Well, coming to the applications, liposomes in combination with hyperthermia are used to treat cancers affecting oesophagus, sarcoma, ovaries, Kaposi sarcoma. However metastases needs whole body hyperthermia. This has some serious side effects. Coming to the materials, MPPC, 1-palmitoyl-2-hydroxy-snglycero-3-phosphocholine; DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine; HSPC, hydrogenated soy sn-glycero-3-phosphocholine; ---> liposome layer formation DSPE-PEG-2000, 1,2-distearoyl-snglycero-3-phosphoethanolamine-N-polyethylene glycol 2000--> ensures higher life span in circulation. Reference: http://cancerres.aacrjournals.org/content/60/5/1197.full.pdf+html Cancers can also be treated using magnetic liposomes along with hyperthermia. You can find more information in MAGNETIC TARGETED CARRIERS - TARGETED DRUG DELIVERY SYSTEM BY HEMANTH

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Harsh bansal's picture

hello sirisha nice presentation i want to know that 1) effect on liposomes in case of fever that is their is high temp then normal and any side effect on fast release during high temp. 2) if the patient is suffering by gastric prob. that is release of acid is more then normal in that case is it work properly if not what could we do for that??? thank you

harsh bansal

Sirisha Pingali's picture

hi harsh thank you for the valuable comment. Pyrexia is different from hyperthermia. Pyrexia is rise in body temperature due to metabolites released by invading organism. This is under control of hypothalamus. Whereas hyperthermia is manual rise in temperature above the physiological range almost to 108o-114oF. Here temperature is raised to allow the release of liposomes. Complete release at a particular cell in one shot is not advisable. This has serious side effects of the drug itself. So the formulation is designed in such a way that it releases the drug at controlled rates. Since my topic is related to cancer therapy, i am giving you general answer with respect to this. We know the major side effect in using antineoplastics is they cause gastro intestinal disturbances due to eruption of GI lining. So before treatment if the patient is suffering from gastric problem, this must be treated first. For Cancers of stomach and other parts like peritoneum, Continuous Hyperthermic Peritoneal perfusion CHPP is applied. Ref.: Source: http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Harsh bansal's picture

hello thanks for ans. its almost near the point but you said the formulation is designed in such a way that it releases the drug at controlled rates. can u explain it details what is the way? thank you

harsh bansal

Sirisha Pingali's picture

hello harsh.. thank you for the valuable comment... I apologize you for missing a word while typing. The drug is released at temperature controlled rates. The temperature of the formulation was kept constant using water bath app.37oC. The amount of drug released is noted at this temperature. Now, the temperature is raised to 39oC and the drug release is noted. This is the funda for noting the amount of drug released when the temperature is hiked. At higher temperatures, the drug released is 'x' times higher than the normal mode. This 'x' may be 15 10 or even 2 depending on the formulation. For eg. the drug released from dextran coated temperature sensitive liposomes is 15 times higher at 39oC than the normal one at 37oC. This laid a keystone for the researchers to focus on hyperthermia. Because of its internal research, all these are just clinical trials proved in rats and hamsters. Detailed information and study on man is yet to be done.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Sandeep Reddy's picture

thank you and all the best
Sirisha Pingali's picture

thank you..wish you good luck!!

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Anil kumar appapurapu's picture

power point questions 1.how liposomes used in Heavy metal poisoning? give the mechanism 2.what are the various Hurdles of chemotherapy and radiation and advantages of this system in cancer

anilkumar

Sirisha Pingali's picture

hi anil thank you for the valuable comment Liposomes are mainly used as anticancer agents In heavy metal poisoning in cosmetics. In heavy metal poisoning, the charged chelating agent is entrapped within the liposome. These liposomes were taken up by the cells releasing the encapsulated agent-->Complexation process-->More soluble complex-->draining from the body. In cosmetics, the liposomes are used to retain the preparation to the outer layers of skin. Lets talk about the advantages first. Using thermosensitive liposomes the major positive thing is they cause minimal damage to non cancerous cells unlike the common chemotherapy and radiation methods. Hurdle in the present system of cancer therapy is myelosuppression, Hair loss, Emesis and so many. Major side effects can be reduced if the targeting is done to cancerous cells alone.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

How is improved therapeutic index achieved when there is improved metabolism? Can you give me any examples of multi vesicular systems?
Sirisha Pingali's picture

hello arun kumar thank you for the valuable comment. Therapeutic ratio is the ratio of amount of drug that produces therapeutic effect to the amount that produces toxic effect. Higher therapeutic index is always preferred. Improved metabolism to convert complex molecules into simpler ones. Improved therapeutic index to achieve better therapeutic effect of the drug. Both are in different scenarios. quaternary amine salt such as behentrimonium methosulfate used at a level of from 0.1% by weight when used as an emulsifier can produce MVS

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

How is it useful in Poisonings? what is the retention time of Cosmetics over the skin? If retention time is more then it cause irritation to skin? How this draw back is over comed?
Sirisha Pingali's picture

hi arun kumar Liposomes are used in poisoning. In this case, the charged chelating agent is encapsulated in the liposomes --> complexation process--> producing more soluble compound--> elimination from the body. Coming to cosmetics keep aside the retention time. The main application of liposomes in cosmetics is AGEING. I hope you ve watched the new PONDS AND OLAY advertisements. Liposomes are used because the lipids get hydrated --> reduce drying of skin which is an early sign of ageing. Also liposomes are source to replenish lipids eg linoleic acid. Furthur information can be dealt in following link: http://www.dr-baumann-international.co.uk/science/Applications%20of%20Li... Retention times are measured using HPLC.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

Is it suitable for practicing through out the world population? i.e Difference in geographical temperatures? With in how much time the process is completed?
Sirisha Pingali's picture

hi arun kumar thank you for the valuable comment Yes the technique is practiced all over the world. Infact, few people buy the ultrasound hyperthermia machine equipment. Good example is the following link where the man himself narrates his own story. nickshealth.blogspot.com/ Well, there is a time limit because excess vibrations may cause boils, blisters etc. However the time is selected based on stage of the cancer.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

In one of your slide liposomes re leave irritation, then during hyperthermia due to the negative feed back mechanism it causes sweating, which means finally irritation? then??????????
Sirisha Pingali's picture

hello arun kumar thank you for the valuable comment Irritation here is the GI irritation which is a common side effect in chemotherapy. Whenever you raise the temperature definitely sweat is produced. This is the same thing in hyperthermia too.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

Due to local or systemic hyperthermia there is disturbances in enzymatic action how is this over come ? Is there any effect in pH of stomach?
Sirisha Pingali's picture

hi arun kumar thank you for the valuable comment When the temperature is raised, the enzymatic activity is increased as we know. THis rise is continued upto threshold level. Local hyperthermia has a minimal action whereas systemic hyperthermia (Whole body hyperthermia) has vascular and cardiac side effects. So generally it is not practiced. As i said earlier, pH is determined whenever temperature is noted and it is designated as eg. pH 2.5 at 22oC So the patients with gastric acidity should be constantly monitored to combat the serious consequences.

Sirisha Pingali

http://www.pharmainfo.net/sirisha

Viswanadha Institute of Pharmaceutical Sciences.

www.vnips.edu.in

Arun Kumar Palle's picture

I could not see the slide no. so could not mention the slide, in one of your slide you mentioned PEG? which type of PEG is used mostly?

Pages

You May Also Like..