Using multiple drugs bonded tightly to a nanodrug “transport vehicle”, it is possible to attack breast cancer cells from the inside and target specific molecules that help tumors grow and spread, while leaving healthy cells intact, according to researchers at Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute in Los Angeles, California.
Unlike other drugs that target cancer cells from the outside, often with minimal effect, using lab mice, the Cedars-Sinai researchers have shown that the nanodrug they have developed, which belongs to an emerging class called nanobiopolymeric conjugates, or nanoconjugates, allows specific tumor-targeting chemicals to accumulate inside tumor cells and strike specific mechanisms inside the most challenging breast cancer cells.
Earlier work with nanoconjugates at Cedars-Sinai has established that a similar approach also works in attacking malignant brain tumors.
Dr Julia Y Ljubimova, senior author of an article about the work in a recent issue of Cancer Research, explained to the press the many ways that nanobiopolymers enhance cancer cell targeting and treatment:
“Certain antibodies can be attached to precisely target proteins in tumor cells; drug resistance and systemic side-effects are reduced because drugs are ‘bound’ to the platform and delivered to the interior of cancer cells without affecting healthy cells; and multiple drugs can be carried on a single platform, making it possible to simultaneously attack several targets,” said Ljubimova, who directs the Drug Delivery and Nanomedicine Laboratory in the Department of Neurosurgery at Cedars-Sinai.
The researchers have conducted a number of studies, using lab mice, to show that this highly targeted approach, using a combination of drugs, is more effective than current standard treatments.
In their latest work on breast cancer, the researchers targeted HER2-positive breast cancer. In this type of breast cancer, women who carry a mutant form of a gene have more HER2 receptors on the surface of cancer cells, causing them to grow more quickly than other types of breast cancer.
HER2-positive breast cancers tend to be more aggressive and less responsive to treatment. The antitumor drug Herceptin (generic name trastuzumab) can sometimes help, but it carries risks as well as benefits.
Herceptin works by binding to the HER2 receptors on the surface of cancer cells and stops them signaling the cell to grow and divide; it also allows immune system killer cells to attach themselves to it when bound to the receptor and kill the tumor cell.
However, the effectiveness of Herceptin is limited by the fact that in 66 to 88% of patients, the tumors become resistant within 12 months of treatment. It can also injure normal organs that it comes into contact with, said the researchers.
The hope is that new drug technology based on nanopolymers will overcome some of these problems and offer great potential in cancer therapy.
In their recent Cancer Research paper, Ljubimova and colleagues describe how they tested their polymalic acid (PMLA) nanobiopolymer in mice implanted with human breast cancer cells and found the drugs accumulated in the cancer cells and significantly reduced tumor growth.
The PMLA nanoplatform, which they describe as “biodegradable, nontoxic, and nonimmunogenic”, carries a number of molecules, including Herceptin, each with a distinct role. The Herceptin targets existing HER2 protein, another molecule targets the genetic mechanism that triggers production of new protein, and a third molecule causes tumor blood vessels to open and allow the nanodrug transporter to enter the cancer cell and release its payload.
“Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system,” write the authors.
An important feature of nanoconjugates is the tight chemical bonds that prevent the active drug components getting damaged or separated in tissues or in the blood as they find their way to the tumor.
Another important feature, a result of inventive drug engineering, is that the drugs don’t become active until they are inside tumor cells. This ultimate assault is a well-choreographed cascade of biochemical events that starts with homing in on tumor cells, passing through the blood vessel and cell walls, releasing the antitumor drugs at the right place and at the right time, and then dismantling the mechanisms that help the blood vessels feed the tumor cells.
Ljubimova said their studies show their nanobioconjugate is safe and efficient and can be tailored to treat a range of disorders.
“It is harmlessly degraded to carbon dioxide and water, nontoxic to normal tissue, and, unlike some drugs, it is non-immunogenic, meaning it does not stimulate the immune system to the point of causing allergic reactions, which may range from mild coughs or rashes to sudden, life-threatening symptoms,” she added.
Ljubimova and two fellow researchers have declared a financial interest in a company that has a stake in this technology.
Funds for the current study came from the National Institutes of Health, the Winnick Family Foundation, and the Department of Neurosurgery at Cedars-Sinai Medical Center.
Support for future studies on the nanoconjugate at Cedars-Sinai’s nanomedicine research laboratory includes a five year grant from the National Cancer Institute as part of its Nanotechnology in Cancer Program.
“Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity.”
Satoshi Inoue, Hui Ding, Jose Portilla-Arias, Jinwei Hu, Bindu Konda, Manabu Fujita, Andres Espinoza, Sonal Suhane, Marisa Riley, Marcus Gates, Rameshwar Patil, Manuel L. Penichet, Alexander V. Ljubimov, Keith L. Black, Eggehard Holler, and Julia Y. Ljubimova.
Cancer Res 15 February 2011 71:1454-1464
DOI:10.1158/0008-5472.CAN-10-3093
Additional source: Cedars-Sinai Medical Center (29 Mar 2011).
Written by: Catharine Paddock, PhD