A unique nanoscale drug that can carry a variety of weapons and sneak into cancer cells to break them down from the inside has a new component: a protein that stimulates the immune system to attack HER2-positive breast cancer cells.

The research team – led by scientists at the Nanomedicine Research Center, part of the Maxine Dunitz Neurosurgical Institute in the Department of Neurosurgery at Cedars-Sinai Medical Center – conducted the study in laboratory mice with implanted human breast cancer cells. Mice receiving the drug lived significantly longer than untreated counterparts and those receiving only certain components of the drug, according to a recent article published in the Journal of Controlled Release.[1]


This …. approach directly kills cancer cells, blocks the growth of cancer-supporting blood vessels and stimulates a powerful antitumor immune response


Researchers from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, the Division of Surgical Oncology at UCLA, and the Molecular Biology Institute at UCLA also participated in the study. Unlike other drugs that target cancer cells from the outside, often injuring normal cells as a side effect, this therapy consists of multiple drugs chemically bonded to a “nanoplatform” that functions as a transport vehicle.

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Promoting cancer growth
HER2-positive cancers – making up 25 to 30% of breast and ovarian cancers – tend to be more aggressive and less responsive to treatment than others because the overactive HER2 gene makes excessive amounts of a protein that promotes cancer growth. One commonly used drug, trastuzumab, (Herceptin; Genentech/Roche), often is effective for a while, but many tumors become resistant within the first year of treatment and the drug can injure normal organs it contacts.

Trastuzumab is an Antibody
But trastuzumab is an antibody to the HER2 gene – it naturally seeks out this protein – so the research team used key parts of trastuzumab to guide the nanodrug into HER2-positive cancer cells.

“We genetically prepared a new ‘fusion gene’ that consists of an immune-stimulating protein, interleukin-2 (IL-2), and a gene of trastuzumab,” said Julia Y. Ljubimova, MD, PhD, professor of neurosurgery and biomedical sciences and director of the Nanomedicine Research Center. “IL-2 activates a variety of immune cells but is not stable in blood plasma and does not home specifically to tumor cells. By attaching the new fusion antibody to the nanoplatform, we were able to deliver trastuzumab directly to HER2-positive cancer cells, at the same time transporting IL-2 to the tumor site to stimulate the immune system. Attaching IL-2 to the platform helped stabilize the protein and allowed us to double the dosage that could be delivered to the tumor.” This nanodrug directly targets breast cancer cells from inside the cell, blocking the growth of cancer-supporting blood vessels and stimulating an antitumor immune response.

Interleukin-2
IL-2 is a naturally occurring cytokine, first identified in 1976, that is produced by activated T lymphocytes (T helper cells) in response to antigenic or mitogenic stimulation. As their name suggests, the interleukins act as molecular communicators between leucocytes. IL-2 has a range of immunomodulatory activities that are central to the body’s direct cytotoxic and antibody-dependent (humoral) immune responses. These include stimulation and activation of other cytotoxic T lymphocytes, B lymphocytes, natural killer (NK) cells and macrophages. IL-2 also induces the release of numerous cytokines (the so-called cytokine cascade), including tumour necrosis factor (TNF), gamma interferon (IFN γ) and other interleukins.[2]

Ljubimova led the study with Manuel Penichet, MD, PhD, associate professor of surgery, microbiology, immunology and molecular genetics at the University of California, Los Angeles, David Geffen School of Medicine. Ljubimova said the UCLA collaborators developed the fusion gene, and Cedars-Sinai chemists Eggehard Holler, PhD, professor in the Department of Neurosurgery, and Hui Ding, PhD, assistant professor, performed the technically difficult task of attaching it to the nanoplatform. Ding is the journal article’s first author.

The researchers also attached other components, such as molecules to block a protein (laminin-411, formerly known as laminin-8) that cancer cells need to make new blood vessels for growth. Studies have shown that abnormal interactions between cancer cells and laminin are major traits of malignant disorders.

Altering defined targets
The nanodrug, Polycefin™ is in an emerging class called nanobiopolymeric conjugates, nanoconjugates or nanobioconjugates. It is part of a molecular biopolymer engineered to interrupt the changes in blood vessels that allow tumors to develop and specific targets genes coding for laminin-411 which influence the thin basement membrane, the structural component of the blood vessels. Polycefin, which may offer the first therapeutic approach aimed at blood vessel changes for multiple chain proteins such laminins and collagens acts as a drug itself but also can be engineered to transport other therapeutic molecules, possibly leading to the creation of highly potent, patient-specific treatment options. Polycefin is intended to slow their growth by entering cells and altering defined targets.

The platform of the drug is ultra-purified polymalic acid derived from the slime mold. It appears to be completely and harmlessly “digested” by the body after serving its purpose, leaving no residue behind. The researchers also observed that in laboratory and animal studies, Polycefin was able to cross the blood-tumor-brain barrier and accumulate in cancer cells. According to the researchers this suggests that the this drug candidate may be used to target brain tumors without affecting normal surrounding tissue.

Commenting on these findings, Ljubimova said: “The new version also stimulates the immune system to further weaken cancers. “We believe this is the first time a drug has been designed for nano-immunology anti-cancer treatment.”

Bioconjugates
Bioconjugates are drugs that contain chemical “modules” attached (conjugated) to a delivery vehicle by strong chemical bonds. The nanoconjugate exists as a single chemical unit, and the tight bonds prevent the components from getting damaged or separated in tissues or blood plasma during transit. With inventive drug engineering, the anti-tumor components activate inside tumor cells.

“More study is needed to confirm our findings, improve the effectiveness of this approach and shed light on the anti-cancer mechanisms at work, but it appears that the nanobioconjugate may represent a new generation of cancer therapeutics in which we launch a multipronged attack that directly kills cancer cells, blocks the growth of cancer-supporting blood vessels and stimulates a powerful antitumor immune response,” Ljubimova said, adding that this and previous animal studies have found the nanodrug to be a safe and efficient delivery platform.

Nano researchers manipulate substances and materials at the atomic level, generally working with substances smaller than 100 nanometers. Cedars-Sinai’s nanoconjugate is estimated to be about 27 nanometers wide. A human hair is 80,000 to 100,000 nanometers wide.

This article was first published online in Onco’Zine – The International Cancer Network [Article]


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