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.
TechnologyOne 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 lipoplatinNanoparticles 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 lipoplatinLipoplatin 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.