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Lipoplatin

Lipoplatin, or Nanoplatin (also known as liposomal cisplatin) is the newest cytostatic anticancer chemotherapeutic drug of alkylating type from the group of platinum preparations, consisting of an suspension of nanoparticles with an average diameter of 110 nanometers.

Technology

One approach that has attracted considerable attention in molecular biology is the development of liposome formulations that can be used in the encapsulation of drugs and other molecules for delivery to the body. Regulon has developed a unique liposome encapsulation technology to overcome obstacles to drug delivery to cancer cells, thereby increasing the effectiveness of cancer therapy tens and even hundreds of times. This method and technology is applied to drugs, small molecules, peptides, proteins and viruses.

The chemical composition of lipoplatin

Nanoparticles in a lipoplatin suspension are liposomes - tiny lipid capsules containing cisplatin molecules inside (Peyrone salts, or cis-dichlorodiammineplatinum (II), cis- [Pt (NH3)2Cl2]). Such a device reduces the toxicity of liposomal cisplatin compared with conventional cisplatin and increases its antitumor activity, which was originally shown in a series of experiments on mice with xenografts of human tumors.

Mechanism of action of lipoplatin

Lipoplatin nanoparticles avoid the body's immune response without being captured by macrophages and cells of the reticuloendothelial system, circulate in biological fluids for a long time after a single intravenous administration with an elimination half-life of about 120 hours, and are capable of extravasation through the damaged vascular endothelium in malignant tumors while destroying tumor vasculature actively reducing the processes of tumor angiogenesis. Thus, due to the above described mechanism of extravasation of liposomes through the damaged tumor endothelium, nanoparticles of lipoplatin have the property of selectively accumulating in the tissue of the primary tumor and its metastases. Studies of human biopsy specimens showed that when using lipoplatin, unlike conventional cisplatin, 20 hours after infusion of the drug in the tumor tissue an extremely high concentration of platinum ions is created, reaching 40-200 times higher than the concentration of platinum ions in neighboring normal healthy tissues, where angiogenesis does not occur as quickly as in a tumor, and where, therefore, the integrity of the vascular endothelium is not compromised. After lipoplatin nanoparticles enter the tumor tissue, these nanoparticles are able to “merge” (to fuse) with tumor cells, due to the abundant presence of a special “fusogenic” lipid, the so-called DPPG, on the surface of the lipid bilayer. An alternative mechanism for delivering lipoplatin nanoparticles inside tumor cells involves active endocytosis with cisplatin liposome tumor cells. The existence and effectiveness of this mechanism of delivery of lipoplatin into tumor cells is proved by experiments in which lipoplatin nanoparticles containing fluorescently colored lipids were introduced into a culture of malignant cells, after which these particles (and the process of their endocytosis) were soon detected inside the tumor cells using the method of fluorescence microscopy . It should be noted that the process of absorption of lipoplatin nanoparticles by tumor cells proceeds much faster and more efficiently than similar processes in normal cells, since the need of tumor cells for nutrients, and in particular for lipids, is extremely large and many times exceeds the metabolic needs of normal healthy cells, and the lipid bilayer of the nanoparticles allows you to “fool” the tumor cell and, under the guise of lipid food, “feed” the cell poisoning it with cisplatin. This technology allows lipoplatin nanoparticles to more or less selectively destroy precisely malignant cells, due to their greater need for nutrients. At the same time, the cell membrane is a serious obstacle to the successful transport of toxic molecules (and in particular cisplatin) to normal, non-liposomal chemotherapy drugs. An additional advantage of liposomal cisplatin over ordinary cisplatin is its increased resistance to one of the mechanisms mediating the development of drug resistance of malignant cells to normal cisplatin, namely, to vacuolization and exocytosis of cisplatin molecules mediated by the work of the so-called “multidrug resistance gene” or MDR- gene (multidrug resistance gene, MDR gene). Tumor cells expressing the MDR gene are less prone to “spitting out” (exocyting) liposomes with cisplatin than conventional cisplatin molecules, since these liposomes are mistakenly considered “food” and not poison. Therefore, tumor resistance to liposomal cisplatin is not developed as quickly as normal

Reducing the side effects of classical chemotherapy.

The half-life of lipoplatin in the blood of patients is about 2-3 days compared with the half-life of cisplatin from the body in 6 hours. Thus, the excretion through the kidneys is significantly lower, which explains the low nephrotoxicity of Lipoplatin. Because of the lipid membrane, lipoplatin does not harm kidney cells and other normal tissues, causing nephrotoxicity and other side effects.
On the contrary, due to its extravasation and its penetration into the cell through fusion with the cell membrane, it increases efficiency while reducing penetration into normal tissues, thereby reducing the side effects of classical chemotherapy with cisplatin (toxicity to the kidneys, bone marrow, peripheral nerves, gastrointestinal tract). Lipoplatin is rapidly phagocytized by tumor cells, bypassing the membrane barrier, which is largely responsible for drug resistance, which usually occurs during 1st line therapy. Delivering the “payload” of cisplatin directly to the tumor cells, facilitated by DPPG fusion, which bypasses the need for Ctr1 receptor-mediated transport, as is the case with cisplatin. After concentration in the tumor and metastatic tissues, DPPG on the surface of lipoplatin promotes its fusion with the cell membrane. Once they reach the goal of the tumor, lipoplatin nanoparticles have a unique advantage for Regulon technology - to merge with the cell membrane of the tumor cell and empty their toxic load inside the cytoplasm. Liposomes developed by others (for example, Doxil or SPI-77 from Alza / J & J) are not able to carry out the fusion process; thus, the toxic drug is excreted outside the tumor cell and is less effective.

Effective passive tumor targeting

Drug encapsulation takes advantage of the chemical structural characteristics of various drugs, especially those used for chemotherapy in cancer patients. Lipoplatin, a liposome-encapsulated form of cisplatin, makes a significant breakthrough in molecular medicine, significantly reducing the toxicity of cisplatin and enhancing its targeting to the tumor after intravenous injection. The encapsulation efficiency achieves an extremely high result, unlike any other similar technology. Passive delivery to a tumor is carried out secretly from immune cells and normal tissues by encapsulating cytotoxic drugs in a capsule of natural lipid protected by a PEG polymer; 110 nm liposome nanoparticles use the compromised endothelium of the tumor vasculature for their predominant extravasation into tumors and metastases. The lipids that make up the shell of nanoparticles are natural products, one of the four classes of biomacromolecules that are compatible with cell membrane lipids, unlike synthetic polymers used in other nanotechnology capsules with questionable cumulative toxicity. Lipoplatin achieved important goals and solved major and unresolved problems in clinical oncology. Lipoplatin nanoparticles loaded with cisplatin are absorbed by tumors and metastases 200 times more than normal (healthy) tissue . In addition, lipoplatin nanoparticles fuse with the cell membrane, releasing their toxic load inside the cell. All these characteristics have not yet been achieved by any chemotherapeutic drug. In addition, Lipoplatin has great synergy with radiation to destroy tumor cells. Finally, lipoplatin nanoparticles are endowed with the potential of antiangiogenesis and antimetastasis, which oncologists are desperately looking for among the drugs, all of them are combined in one nanoparticle together with the classical chemotherapy benefits of cisplatin.

Monotherapy Lipoplatin + RT (high dose lipoplatin) (low dose radiation)

Regulon has come to a revolutionary cancer treatment protocol. The patient receives intravenous lipoplatin infusion; over the next 24 hours, lipoplatin nanoparticles accumulate in the tumors. The next day after lipoplatin, the patient undergoes radiotherapy (receives a low dose of radiation - 2 Gy) in the places of primary lesion and metastasis. When using this protocol, the effectiveness of Lipoplatin is increased by 14-30 times due to the combination of low doses of radiation by increasing the radiosensitizing potential of Lipoplatin, as shown in preclinical studies in Canada. Thus, the new treatment protocol will provide the medical community with medicine that is many times more effective than the queen of chemotherapy with cisplatin (Cisplatin) and without side effects. This will bring a real revolution in cancer treatment. In the image below, a 95% shrinkage of a high-grade osteosarcoma tumor was obtained when the patient was subjected to intensive dose monotherapy with lipoplatin and fractionated radiation for a 25-week period. Our treatment was devoid of toxicity.