Lipoplatin (Liposomal cisplatin) is a

nanoparticle A nanoparticle or ultrafine particle is a particle of matter 1 to 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 100 nm in only two directions. At ...

of 110 nm average diameter composed of

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

s and

cisplatin Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

. This new drug has successfully finished Phase I, Phase II, and Phase III human clinical trials. It has shown superiority to cisplatin in combination with

paclitaxel Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...

as a

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

regimen in

non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

(NSCLC)

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

Mechanism of action

Lipoplatin evades immune surveillance thus escaping clearance from

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s, circulates for long periods in

body fluid Body fluids, bodily fluids, or biofluids, sometimes body liquids, are liquids within the Body (biology), body of an organism. In lean healthy adult men, the total body water is about 60% (60–67%) of the total Human body weight, body weight; it ...

s after intravenous administration with a

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of ~120 h, and

extravasate Extravasation is the leakage of a fluid out of its contained space into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells through the capillary wall, ...

s through the compromised

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

of the

vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s created during the process of neo

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

br>Extravasation Figure
Thus, lipoplatin nanoparticles are concentrated to the

primary tumor A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most solid cancers develop at their primary site but may then go on to metastasize or spread to other parts of the b ...

and

metastases Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

. Human studies have shown 40- to 200-fold higher

platinum Platinum is a chemical element; it has Symbol (chemistry), symbol Pt and atomic number 78. It is a density, dense, malleable, ductility, ductile, highly unreactive, precious metal, precious, silverish-white transition metal. Its name origina ...

concentration compared to the adjacent normal tissue in specimens from human

biopsies A biopsy is a medical test commonly performed by a surgeon, an interventional radiologist, or an interventional cardiologist. The process involves the extraction of sample cells or tissues for examination to determine the presence or extent of ...

20 post-infusion of the drug. Lipoplatin nanoparticles once inside the tumor cell mass can fuse with the cell membrane because of the presence of the fusogenic lipid DPPG in their lipid bilayer; an alternative mechanism proposed is that lipoplatin is taken by endocytosis by tumor cells as shown from lipoplatin containing fluorescent lipids and imaging of the tumor cells in culture thus treated with fluorescent microscopy. These processes occurring at the cell membrane level are promoted by the lipid shell of the nanoparticles (disguised as nutrients). The technology allows lipoplatin to empty its toxic payload (cisplatin) inside the cytoplasm to kill the tumor cell. The cell membrane is considered a significant barrier to transportation of the toxic molecules of cisplatin across and inside the tumor cell.

Trials

The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMEA) gave lipoplatin

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

status in 2007 in an ongoing registrational Phase II/III study as a first line-treatment in

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...

. Under the trade name Nanoplatin, lipoplatin received EMEA consent in 2009 to be tested as a first-line treatment for non-squamous cell

non-small-cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

s (ns-NSCLC) that are mainly composed of adenocarcinomas. The results of a Phase III trial were published in October 2011. This study used lipoplatin in combination with

to treat ns-NSCLC, comparing response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel and demonstrated a statistically significant (‘’p’’-value = 0.036) increase in tumor response rate in the lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42% of patients). Most major toxicities of cisplatin, especially

nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

, were also reduced in the group of patients treated with lipoplatin and treatment did not require hospitalisation for lipoplatin patients. Median survival times were 10 months for the lipoplatin arm and 8 months for the cisplatin arm, with a ‘’p’’-value of 0.155. The median duration of response was 7 months for the lipoplatin arm and 6 months for the cisplatin arm. Although not statistically significant, these results suggest the potential for superior overall survival for lipoplatin compared to cisplatin, a hypothesis that is being tested in a larger trial. Furthermore, among the responders to lipoplatin a subgroup of patients demonstrated a substantially higher overall survival than a comparable subgroup of cisplatin responders. After 10 months, 30% of patients in the lipoplatin arm, as compared with just 16% of patients in the cisplatin arm, were without disease progression. By the end of the trial, there were 32 patients alive, 21 from the lipoplatin arm (20.39%) and 11 from the cisplatin arm (11.11%). Thus, after 18 months, the number of surviving patients was approximately double for lipoplatin versus cisplatin. The clinical development of lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects. Preliminary investigations suggest the potential for lipoplatin to be a suitable agent for targeting

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

in patients with aggressive cisplatin resistance.

References

{{Reflist

Sources

*Boulikas T (2004) Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts. Oncol Rep 12: 3-12, 2004.

External links

*http://www.lipoplatin.com *http://www.regulon.com
Lipoplatin plus gemcitabine versus cisplatin plus gemcitabine in NSCLC: Preliminary results of a phase III trialLiposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trialLipoplatin Formulation Review Article
Platinum-based antineoplastic agents Liposomally encapsulated antineoplastic agents