The Main Reason For Encapsulation Of Doxorubicin Into Liposomes

The main reason for encapsulation of doxorubicin is drug leakage (due to localization loaded in a membrane). The release is very quick. Particles are amorphous in nature. Rapid burst release. The burst release rate is compatible with the dilution release rate. Also, by encapsulation, we are increasing the retention time and circulation time which helps to protect healthy tissues. Problems with the first generation OLV-DOX that causes the failure to obtain FDA approval:

• Drug leakage
• Particle size
• Preferential RES uptake
• Drug loading
• Poor circulation time.
• Drug Payload
• Cardiotoxicity (Cumulative dose-dependent cardiotoxicity).

Drug leakage from circulating liposomes is undesirable and causes cardiotoxicity especially results in heart failure. The solution to the above-mentioned problem that leads to approval:

• EPR effect.
• Increase the circulation time.
• Alter the particle size (Using small enough liposomes (<120nm, preferably <100nm) nano-liposome).
• Loading of Doxil into the core of the liposomes: Drug should be available to tumor cells either by drug release at the tumor site or by the drug-loaded nano-liposomes being internalized by the tumor cells.
• Increase drug loading (Stable loading) to increase the efficacy.
• RES avoidance.
• Extravasation at the tumor site by targeted delivery.
• Remote loading by ammonium sulfate encapsulation enables to deliver enough drug to the tumor which can be released there at therapeutic levels.

Remaining issues with Doxil that need to be addressed:

• Infusion related reaction that leads to the flushing and shortness of breath.
• Accumulation of Doxil causing the blistering effect.
• Effects other healthy sites than tumor especially heart.

The drug is being removed from the indication of diseases such as breast cancer because of the following reason:

• Decrease in mental functioning: Women’s treated with breast cancer may have a certain problem with memory concentration.
• The after-effects of the treatment are worst and causes severe nausea and vomiting, Diarrhea, loss of appetite, weakness, tiredness, eye redness or puffy eyes.
• It causes heart damage.
• Hand-foot syndrome: Doxorubicin causes irritation in palms of the hands and soles of the feet.

Properties of Thermodox

Thermodox is the first drug which uses new technology to produce heat-sensitive liposomes that contains doxorubicin. It is a widely used chemotherapeutic agent. First used in the treatment of primary liver cancer also called Hepatocellular carcinoma. Thermodox with radiofrequency ablation which produces high temperature at the tumor site. Thermodox circulates throughout the body and liver bathing the tumor and surrounding areas with a concentration of doxorubicin.

The physical difference between Thermodox and Doxil

Doxil is the encapsulated form of doxorubicin inside liposome also known as pegylated liposome and Thermodox is the heat sensitive liposomes that contains doxorubicin. Doxil is having a slow and continuous drug release rate whereas Thermodox has fast drug release rate. Thermodox uses heat to activate the liposomes in and around the periphery of the tumor releasing the encapsulated doxorubicin.

Compartment Modeling showing focused heat could potentially improve doxorubicin delivery to tumors from Thermodox in circulation: We use multi-compartment modeling for explaining the mechanism. K1: It is the drug infusion into the blood plasma which is Thermodox (doxorubicin with heat). K2: It is clearance constant (By inactivation/excretion). K2 is generally high for Doxil and will be constant for Thermodox also. K3: The value of K3 will increase because you are changing the permeability of your drug to the tumor space. K4: The value of the K4 will also increase. C1: Blood Plasma C2: Tumor site. Microbubble contrast agent sonoporation for improving Doxil uptake into malignant tissue would be appropriate, as follows: In this, the microbubbles are encapsulated with doxorubicin within a liposome. Ultrasound waves are provided to the microbubbles which will go to the tumor site and as it is heat sensitive liposome it will not harm the healthy tissue and will directly reach the tumor site. The release of drug which is doxorubicin takes place with the help of sonoporation by inertial cavitation. Focused ultrasound can be used to penetrate deep into tissue and can produce a heating effect at the target site. Hyperthermia increases the uptake of drugs. Microbubbles expand and contract as a result of ultrasound pressure.

These oscillation varied from tissue to tissue and due to this, we get different scattered signals. These scattered signals generate detailed images of blood flow and tissue. The signals are non-linear and enhance the contrast. Based on the properties of Doxil stable cavitation is used to improve drug uptake in a non-fenestrated tissue example opening on blood-brain barriers. Stable cavitation is what we use in ultrasound, the bubble keeps oscillating, changing volume produces sounds. Stable cavitation can permeabilize cells vasculature, used to puncture cell membrane that’s why used to open blood-brain barriers.