Bibliographic details of the publications referred to by the author in this specification are collected alphabetically at the end of the description.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Malignant tumours, or cancers, grow in an uncontrolled manner, invade normal tissues, and often metastasize and grow at sites distant from the tissue of origin. In general, cancers are derived from one or only a few normal cells that have undergone a poorly understood process called malignant transformation. Cancers can arise from almost any tissue in the body. Those derived from epithelial cells, called carcinomas, are the most common kinds of cancers. Sarcomas are malignant tumours of mesenchymal tissues, arising from cells such as fibroblasts, muscle cells, and fat cells. Solid malignant tumours of lymphoid tissues are called lymphomas, and marrow and blood-borne malignant tumours of lymphocytes and other hematopoietic cells are called leukaemias.
Cancer is one of the three leading causes of death in industrialised nations. As treatments for infectious diseases and the prevention of cardiovascular disease continues to improve, and the average life expectancy increases, cancer is likely to become the most common fatal disease in these countries. Therefore, successfully treating cancer requires that all the malignant cells be removed or destroyed without killing the patient. An ideal way to achieve this would be to induce an immune response against the tumour that would discriminate between the cells of the tumour and their normal cellular counterparts. However, immunological approaches to the treatment of cancer have been attempted for over a century with unsustainable results.
Accordingly, current methods of treating cancer continue to follow the long used protocol of surgical excision (if possible) followed by radiotherapy and/or chemotherapy, if necessary. The success rate of this rather crude form of treatment is extremely variable but generally decreases significantly as the tumour becomes more advanced and metastasises. Further, these treatments are associated with severe side effects including disfigurement and scarring from surgery (e.g. mastectomy or limb amputation), severe nausea and vomiting from chemotherapy, and most significantly, the damage to normal tissues such as the hair follicles, gut and bone marrow which is induced as a result of the relatively non-specific targeting mechanism of the toxic drugs which form part of most cancer treatments and is a major limiting factor for dosage
Still further, common chemotherapy drugs do not significantly penetrate into tissue further than about 70 microns from the blood supply (Primeau et al. Clin. Canc. Res. 2005, 11:8782-8788; Minchinton et al. Nat. Rev. Cancer 2006, 6:583-592). The rapid growth and poor vascular development of most solid tumours puts many tumour cells well beyond the capacity of the drugs to penetrate the tissue. Critically, many cells experience sub-lethal doses, allowing them to survive and to develop drug resistance.
Solid tumours cause the greatest number of deaths from cancer and mainly comprise tumours of the linings of the bronchial tree and the alimentary tract that are known as carcinomas. In the year 2000 in Australia, cancer accounted for 30% of male deaths and 25% of female deaths (Cancer in Australia 2000, 2003) and it accounted for 24% of male and 22% of female deaths in the US in year 2001 (Arias et al. 2003, National Vital Statistics Reports 52:111-115). Solid tumours are not usually curable once they have spread or ‘metastasised’ throughout the body. The prognosis of metastatic solid tumours has improved only marginally in the last 50 years. The best chance for the cure of a solid tumour remains in the use of local treatments such as surgery and/or radiotherapy when the solid tumour is localised to its originating lining and has not spread either to the lymph nodes that drain the tumour or elsewhere. Nonetheless, even at this early stage, and particularly if the tumour has spread to the draining lymph nodes, microscopic deposits of cancer known as micrometastases may have already spread throughout the body and will subsequently lead to the death of the patient. In this sense, cancer is a systemic disease that requires systemically administered treatments. Of the patients who receive surgery and/or radiotherapy as definitive local treatment for their primary tumour and who have micrometastases, a minor proportion may be cured or at least achieve a durable remission from cancer by the addition of adjuvant systemic treatments such as cytotoxic chemotherapy or hormones.
Conventionally, solid cancer has been treated locally with surgery and/or radiotherapy, and during its metastatic stage with systemically administered cytotoxic drugs, which often interfere with the cell cycle of both normal and malignant cells. The relative selectivity of this approach for the treatment of malignant tissues is based to some extent on the more rapid recovery of normal tissues from cytotoxic drug damage. More recently, the targeted therapy of cancer has aimed to improve the therapeutic ratio of cancer treatment by enhancing its specificity and/or precision of delivery to malignant tissues while minimising adverse consequences to normal non-malignant tissues. Two of the major classes of targeted therapy are (i) the small molecule inhibitors such as the tyrosine kinase inhibitors imatinib mesylate (Glivec®), gefitinib (Iressa®) and erlotinib (Tarceva®), and (ii) the monoclonal antibodies (mAb) such as rituximab (Mabthera®) and trastuzumab (Herceptin®).
In parallel to the development of targeted therapies, combining at least two conventional anti-cancer treatments such as chemotherapy and radiotherapy in novel ways has been another approach to the development of cancer therapeutics. By exploiting synergistic interactions between the different modalities of treatment, combined modality treatment seeks to improve treatment efficacy so that the therapeutic ratio for the combined treatment is superior to that for each of the individual treatments.
Combined modality treatment using external beam radiation and radiosensitising chemotherapeutic drugs such as 5-fluorouracil and cisplatin (chemoradiotherapy) has improved survival in a number of solid tumours such as those of head and neck, lung, oesophagus, stomach, pancreas and rectum because of both improved local tumour control and reduced rates of distant failure (TS Lawrence. Oncology (Huntington) 17:23-28, 2003). Although radiosensitising drugs increase tumour response, they also increase toxicity to adjacent normal tissues, which is especially true of the potent new generation radiosensitisers, gemcitabine and docetaxel. However, decreasing the radiation volume allows cytotoxic doses of gemcitabine to be better tolerated clinically (Lawrence 2003, supra). Chemoradiotherapy may overcome mutually reinforcing resistance mechanisms, which may only manifest in vivo.
Radioimmunotherapy (RIT) is a systemic treatment that takes advantage of the specificity and avidity of the antigen-antibody interaction to deliver lethal doses of radiation to cells that bear the target antigen. Radio-isotopes that emit β-particles (e.g. 131Iodine, 90Yttrium, 188Rhenium, and 67Copper) are usually used to label monoclonal antibodies (mAb) for therapeutic applications. The energy from □-radiation is released at relatively low intensity over distances measured in millimeters (Waldmann, Science 252:1657-1662, 1991; Bender et al., Cancer Research 52:121-126, 1992; O'Donoghue et al. Journal of Nuclear Medicine 36:1902-1909, 1995; Griffiths et al. International Journal of Cancer 81:985-992, 1999). Thus, high-energy □-emitters such as 90Yttrium are useful for the treatment of larger and heterogeneous solid tumours (Liu et al. Bioconjugate Chemistry 12:7-34, 2001). Research interest in radioimmunotherapy has been reawakened because in spite of the low radiation doses delivered, significant and unexpected biological effects of RIT upon surrounding host cells have been observed (Xue et al. Proceedings of the National Academy of Sciences of the United States of America 99:13765-13770, 2002). Furthermore, the lower but biologically effective dose of radiation delivered by RIT had greater cytocidal effects than a larger dose of radiation conveyed as external beam radiotherapy (Dadachova et al., PNAS 101:14865-14870, 2004). Nonetheless, the efficiency of RIT as a treatment for solid tumours may be hampered by the low penetration of antibody through the tissue barriers that surround the target antigen in the tumour, which will consequently extend circulatory half life of the antibody (Britz-Cunningham et al. Journal of Nuclear Medicine 44:1945-1961, 2003). Furthermore, RIT is often impeded by the heterogeneity of the target antigen's expression within the tumour. Thus, although RIT affords molecular targeting of tumour cells, the major limitation of RIT remains the toxicity that may result from large doses of radiation that are delivered systemically in order to achieve sufficient targeting (Britz-Cunningham et al. 2003, supra; Christiansen et al. Molecular Cancer Therapy 3:1493-1501, 2004). Altogether, a useful therapeutic index using RIT has proven difficult to achieve clinically (Sellers et al. Journal of Clinical Investigation 104:1655-1661, 1999).
Tumour associated antigens, which would allow differential targeting of tumours, while sparing normal cells, have also been the focus of cancer research. Although abundant ubiquitous antigens may provide a more concentrated and accessible target for RIT, studies adopting this have been extremely limited.
The development of nanoparticle technology was also hailed as an exciting new frontier in terms of the development of new and effective cancer treatments. However, although previous attempts at using particulate material, such as nanoparticles, to target tumours for either diagnostic or therapeutic purposes have been extensive, in the context of therapeutics there has, disappointingly, been minimal success. With diagnostics, relatively shallow penetration of the particles into the tumour has been sufficient to achieve the objective of visualising the tumour. However, in terms of the delivery of a therapeutic agent, such shallow penetration has not been sufficient to effectively deliver the agent throughout the tumour, in particular to the interior of the tumour, as is required if total tumour destruction is to be achieved. In relation to therapeutics, specifically, conjugation of particles to a wide variety of different materials has so far failed to live up to the promise of achieving effective tumour penetration, this being an essential prerequisite for a therapeutic to have any chance of effectiveness.
Significant effort has also been made to take advantage of the enhanced permeability and retention (EPR) effect of tumours as a means to develop an effective therapeutic. Without limiting the present invention to any one theory or mode of action, this is a well described phenomenon based on the notion that certain sizes of molecules, typically liposomes or macromolecular drugs, tend to preferentially accumulate in tumour tissue. The general explanation for this phenomenon is that, in order for tumour cells to grow quickly, they must stimulate the production of blood vessels. VEGF and other growth factors are involved in cancer angiogenesis. Tumour cell aggregates of sizes as small as 150-200 μm become dependent on blood supply carried by neovasculature for their nutritional and oxygen supply. These newly formed tumour vessels are usually abnormal in form and architecture. They comprise poorly-aligned defective endothelial cells with wide fenestrations, lacking a smooth muscle layer, or innervation with a wider lumen, and impaired functional receptors for angiotensin II. Furthermore, tumour tissues usually lack effective lymphatic drainage. All these factors will lead to abnormal molecular and fluid transport dynamics, especially for macromolecular drugs. Accordingly, it has been thought that one way to achieve selective drug targeting to solid tumours is to exploit these abnormalities of tumour vasculature in terms of active and selective delivery of anticancer drugs to tumour tissues, notably defining the EPR effect of macromolecular drugs in solid tumours. Due to their large molecular size, nanosized macromolecular anticancer drugs administered intravenously escape renal clearance. Often they cannot penetrate the tight endothelial junctions of normal blood vessels, but they can extravasate in tumour vasculature and become trapped in the tumour vicinity. Nevertheless, the EPR effect has not been efficiently or successfully harnessed.
Various nanoparticles have been designed which are directed to achieving efficient cellular endocytosis. However, even if this is achievable, the issue of tissue penetration is still a separate one which, to date, has not been successfully overcome. The general notion of the use of a nanoparticle as a vector for delivery of a drug is widely discussed in the literature but, in the absence of achieving deep tumour penetration, is of limited value.
Even where effective tumour distribution of a drug is achieved (by whatever means) a further problem has been the fact that neoplastic cells within solid tumours can exhibit a slowed metabolism. This means that even if a cytotoxic drug penetrates to these cells, if it is not effectively metabolised it will have a limited impact on the viability of the tumour.
Accordingly, there is an urgent and ongoing need to develop improved systemic therapies for solid cancers, in particular metastatic cancers.
In work leading up to the present invention it has been determined that particulate material which is maintained in a dispersed state by a stabiliser is able to achieve deeper penetration into solid tumour models than has previously been achievable using nanoparticle technology. This has enabled the development of an effective means for treating solid tumours, both primary and metastatic, based on the co-administration of a cellular toxin with the particulate material. By either sequentially or simultaneously delivering this toxin, deeper penetration and therefore more extensive cellular exposure to the toxin is achieved. By virtue of the less effective reticuloendothelial clearance which is associated with tumours, a form of targeted treatment is effectively achieved. Still further, it has been observed that the toxin uptake by tumours penetrated by the particles of the present invention is effective, suggesting upregulation of tumour cell metabolism. Accordingly, the method of the present invention provides a means for achieving a more effective localised delivery and uptake of a cellular toxin to a tumour and its metastases in a manner which is characterised by significantly improved outcomes and/or reduced side effects relative to those which would normally be expected in the context of conventional treatment of an equivalent type of tumour. This is an extremely significant development since current protocols directed to treating metastatic disease are based on the non-targeted systemic delivery of chemotherapeutic agents.