"Minicells" May Be the Best Way to Deliver Cancer Medication/Engeneic
By Halina Z.
Published May 09, 2007
Cancer patients may soon receive their chemotherapy treatments by "mini-cells", which would minimize the side effects common to anti-cancer medication. In this week's issue of the journal Cancer Cell, Himanshu Brahmbhatt and Jennifer MacDiarmid, of EnGeneIC Pty. Ltd., in Sydney, Australia, report on the creation of agents termed EnGeneIC Delivery Vehicles (EDVs). EDVs are drug delivery vehicles which are made from bacteria, loaded with the anti-cancer drug of choice, and then injected into the patient. Because the vehicles contain antibodies specific to the cancer itself, they release their payload only upon encountering actual tumors, not healthy tissue.
During normal bacterial cell division, the single bacterium splits down the middle to become two "daughter" bacteria, both of equal size. In the case of EDVs, the EnGeneIC researchers have found a way to promote unequal bacterial division, whereupon the bacterium splits at its end, forming small cytoplasmic "buds". These "buds", measuring an average of 400 nanometers (nm) in size, contain no genetic material, and so do not infect and multiply in the host organism.
Antibodies are then attached to the EDVs, enabling them to target a specific tissue. In the case of breast cancer, the Her2 antibody is attached to the EDVs, allowing them to bind Her2-expressing breast tumor tissue. "Within 2 hours of intravenous administration greater than 30% of the dose ends up in the tumour microenvironment" states Brahmbhatt.
Once bound, the EDVs are internalized by the cells and broken down, whereupon they release their toxic compounds. This is helpful not only in terms of poisoning the tumor, but also for minimizing the amount of drug required to help the patient.
There are additional uses for EDVs beyond simple drug delivery. The vehicles may also be used to transport RNAi, a molecule involved in gene silencing via destruction of an organism's messenger RNA (mRNA). One example of the benefits of RNAi is that cancers previously resistant to various drug treatments, due to production of mRNA which codes for a resistance protein, may be rendered sensitive again.
Experimental trials on pigs and monkeys have shown no toxicity or immune reaction to the EDVs. EnGeneIC hopes to begin running human trials by the end of this year.
The search for targeted delivery vehicles for both chemotherapeutic and radiotherapeutic agents is not new. Stavroula Sofou and her colleagues have been working on liposome-based vehicles for some time now. Sofou's group generated antibody-linked liposomes in the range of 50-100 nm in size and infused them with radioactive alpha particle generators. The liposomes were tested on animals positive for cancer and found to shrink their tumors without inducing whole body toxicity to the alpha particle radiation. Furthermore, fewer alpha particle generators had to be used overall compared with animals not being treated with the liposomes.
Sources:'Mini-cells' could stop side-effects of chemotherapy newscientist.com [[See article below]]
Bacterially Derived 400 nm Particles for Encapsulation and Cancer Cell Targeting of Chemotherapeutics. J. MacDiarmid, N. Mugridge, J. Weiss, L. Phillips, A. Burn, R. Paulin, J. Haasdyk, K. Dickson, V. Brahmbhatt, S. Pattison. Cancer Cell, Volume 11, Issue 5, Pages 431-445.
Engineered Liposomes for Potential alpha-Particle Therapy of Metastatic Cancer Stavroula Sofou, PhD, James L. Thomas, PhD, Hung-yin Lin, PhD, Michael R. McDevitt, PhD, David A. Scheinberg, MD, PhD and George Sgouros, PhD. Journal of Nuclear Medicine Vol. 45 No. 2: 253-260.
associatedcontent.com
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'Mini-cells' could stop side-effects of chemotherapy
17:00 07 May 2007
NewScientist.com news service
Linda Geddes, Boston
Could bacteria be the future of cancer therapy? It may sound unlikely, but mini-cells have been created that can carry high-dose combinations of drugs to exactly where they are needed without releasing them into the general circulation.
They could be adapted to target virtually any tumour tissue in the body, and could put an end to many of the toxic side effects associated with chemotherapy drugs because they do not release their payload until they are inside the target cell. This also means that far less drug is required.
When bacteria divide, they normally do so at their centres. But Himanshu Brahmbhatt and Jennifer MacDiarmid, of EnGeneIC in Sydney, Australia, have found a way of forcing them to divide at their ends, producing small buds of cytoplasm each time. They have also discovered that a range of different drugs could be packaged into these particles. These "mini bacteria", or EnGeneIC Delivery Vehicles (EDVs) as the company has dubbed them, are cheap and easy to produce, and can be used as targeted drug delivery vehicles.
"They look like bacteria but they have no chromosomes and are non-living," says MacDiarmid. "And because they have a rigid membrane they don't break down when injected, so they carry their payload happily to the target site."
On target
The EDVs are able to selectively target different tissues thanks to bispecific antibodies attached to their surface. One arm of the antibody is specific to the EDV and is connected via a linker molecule to the second antibody, which is specific to a protein on the target tissue - for example, the Her2 receptor on breast cancer cells, which is also targeted by Herceptin.
Targeting is also aided by the fact that the blood vessels supplying cancer cells are often leaky, and by coincidence the 400 nanometre EDVs are the perfect size to fall through these holes into the tumour tissue. "Within 2 hours of intravenous administration greater than 30% of the dose ends up in the tumour microenvironment" says Brahmbhatt, who presented the findings at RNAi 2007 in Boston, Massachusetts, on 3 May.
Once EDVs bind to the correct cells, they are internalised and broken down - releasing the drug into the cell, where it can take effect.
To test whether EDVs could deliver drugs to tumours within the body, MacDiarmid and Brahmbhatt packaged a cancer drug called doxorubicin into EDVs, which were targeted to human breast, leukaemia and ovarian tumours. They then injected them into mice xenografted with these tumour types.
The treatment resulted in highly significant inhibition of tumour growth compared to untreated mice, while much lower doses of the drug were required compared to when doxorubicin was administered directly. Similar results were obtained with other chemotherapeutic and molecularly targeted drugs.
Easy to load
Dogs with advanced non-Hodgkin's lymphoma demonstrated significant tumour regression when given targeted EDVs containing doxorubicin, and safety tests in pigs and monkeys have shown no sign of toxicity or significant immune reaction against the EDVs so far. EnGeneIC hopes to begin human trials towards the end of 2007.
"We haven't yet found a drug that you couldn't load," says MacDiarmid, and EnGeneIC believes EDVs could enable cancer patients to be given high doses of multiple drugs, thus increasing the chances of finding one that works for them. Oncologists are often reluctant to prescribe multiple drugs because of the risk of serious side effects - and if they do they will usually reduce the doses to limit the toxicity.
"The amount of drug given with EDVs is thousands of fold less than if they were given directly," says Bruce Stillman, director of Cold Spring Harbor Laboratory in New York, US, and an advisor to the EnGeneIc team. "This, coupled with the fact that you can also target the drugs directly to the target tissue, means that the reduction in side effects could be extraordinary."
Preliminary results in mice also suggest that EDVs could also be used to deliver novel therapies like RNA interference (RNAi), where one of the major hurdles is finding a targeted delivery method.
EDV-packaged short hairpin RNAs, designed to knock out production of a protein that causes multi-drug resistance, reversed resistance to doxorubicin in mice transplanted with human uterine cancer grafts.
Bacterial nanoparticles are a very interesting concept, says Johannes Fruehauf, an expert in cancer and RNAi at Beth Israel Deaconess Medical Centre in Boston, US: "Previous efforts to develop targeted nanoparticles have focused on synthetic methods, which are very expensive. Here they are using bacteria like little biorobots."
Journal reference: Cancer Cell (vol 11, p 431)
Cancer - Learn more about one of the world’s biggest killers in our comprehensive special report.
newscientist.com
Ref:
1 DELIVERING FUNCTIONAL NUCLEIC ACIDS TO MAMMALIAN CELLS VIA BACTERIALLY DERIVED, INTACT MINICELLS in my patents list
Inventor: MACDIARMID JENNIFER (AU); BRAHMBHATT HIMANSHU (AU) Applicant: ENGENEIC GENE THERAPY PTY LTD (AU)
EC: IPC: C12N15/63; A61K48/00; C12N15/63 (+1)
Publication info: CA2577938 - 2006-03-02
2 COMPOSITIONS AND METHODS FOR TARGETED IN VITRO AND IN VIVO DRUG DELIVERY TO MAMMALIAN CELLS VIA BACTERIALLY DERIVED INTACT MINICELLS in my patents list
Inventor: BRAHMBHATT HIMANSHU (AU); MACDIARMID JENNIFER (AU) Applicant: ENGENEIC MOLECULAR DELIVERY PT (AU)
EC: A61K9/50H8B; A61K47/48W2 IPC: A61K47/00; A61K47/00
Publication info: EP1718338 - 2006-11-08
3 TARGETED GENE DELIVERY TO NON-PHAGOCYTIC MAMMALIAN CELLS VIABACTERIALLY DERIVED INTACT MINICELLS in my patents list
Inventor: MACDIARMID JENNIFER (AU); BRAHMBHATT HIMANSHU (AU) Applicant: ENGENEIC MOLECULAR DELIVERY PT (AU)
EC: IPC: A61K47/00; A61K48/00; C12N15/09 (+5)
Publication info: CA2549840 - 2005-06-23
4 Pharmaceutically compatible method for purifying intact bacterial minicells in my patents list
Inventor: JENNIFER BRAHMBHATT HIMANSHU M (AU) Applicant: ENGENEIC MOLECULAR DELIVERY PT (AU)
EC: C12N1/02; C12N1/20 IPC: C12N1/02; C12N1/20; C12N5/02 (+3)
Publication info: CN1809629 - 2006-07-26
5 INTACT MINICELLS AS VECTORS FOR DNA TRANSFER AND GENE THERAPY IN VITRO AND IN VIVO. in my patents list
Inventor: JENNIFER MACDIARMID (AU) Applicant: ENGENEIC MOLECULAR DELIVERY PT (AU)
EC: IPC: C12N15/85; C12N15/85; (IPC1-7): C07K0/00 (+1)
Publication info: MXPA04003493 - 2005-07-25
6 INTACT MINICELLS AS VECTORS FOR DNA TRANSFER AND GENE THERAPY IN VITRO AND IN VIVO in my patents list
Inventor: BRAHMBHATT HIMANSHU (AU); MACDIARMID JENNIFER (AU) Applicant: ENGENEIC GENE THERAPY PTY LTD (AU)
EC: A61K48/00B; C12N15/87 IPC: C12N15/09; A61K38/16; A61K48/00 (+10)
Publication info: EP1446489 - 2004-08-18
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