Nanosized delivery systems for radiopharmaceuticals
The aim of this CRP is to provide significant improvement in the delivery of therapeutic radiopharmaceuticals through the use of nanotechnology. The ability of nano sized, radioactive and targeted nano materials to deliver optimum therapeutic payloads at tumor sites, as envisaged in this CRP, adresses the most important 'unmet clinical need' in nuclear medicine. Such radioactive nanoceuticals will advance the field of oncology because targeted nano constructs built from polymeric nano particles could be potentially capable of reaching the tumor sites selectively and to penetrate tumor vasculature due to their unique intrinsic physical and chemical properties dictated by their nanoscalec dimensions, thus affording highly effective molecular imaging and therapeutic tools to combat various forms of human cancers.
This CRP was formulated based on the conclusions and recommendations of a Consultants Meeting (27 - 31 May 2013), and will utilize the knowledge and expertise in synthesizing polymer nanoparticles using radiation technologies developed under the framework of a completed CRP „Nanoscale Radiation Engineering of Advanced Materials for Potential Biomedical Applications”. It is expected to result in new nanoceuticals, nanoparticles capable of forming stable bonds with diagnostic and therapeutic radioisotopes, and with tumor specific biomolecules and proteins (including monoclonal antibodies) leading to well-defined delivery devices. The proposed CRP will provide tremendous benefits to MS because the nanosized diagnostic and therapeutic agents that are planned to be developed might be potentially used in alleviating pain and suffering of human patients globally.
Background Situation Analysis
Nuclear medicine is an important medical specialty involving the application of radioactive substances in the diagnosis and treatment of diseases. There are a number of diagnostic and therapeutic radiopharmaceuticals that are FDA approved for use in human patients. These radiopharmaceuticals, once administered to the patient, can localize to specific organs or cellular receptors. This property of radiopharmaceuticals allows nuclear medicine the ability to image the extent of a disease process in the body, based on the cellular function and physiology, rather than relying on physical changes in the tissue anatomy. Nuclear medicine has the ability to identify medical problems at an earlier stage than other diagnostic tests. Nuclear medicine is often compared to "radiology done inside out", or "endo-radiology", because it records radiation emitting from within the body rather than radiation that is generated by external sources such as X-rays. The therapeutic effect of radiopharmaceuticals relies on the tissue-destructive power originating from the emission of massive, short-range ionizing radiation by some selected radionuclides. The combined use of a pair of diagnostic and therapeutic radiopharmaceuticals for the treatment of the same disease constitutes the basic paradigm of the field of theranostic as applied to nuclear medicine.
Currently used diagnostic PET and SPECT agents in Nuclear Medicine utilize radiolabelled small-molecules, proteins and peptides as targeting vectors. On the therapy front, β-emitting radionuclides conjugated with tumor specific peptides or monoclonal antibodies, are routinely used to ablate tumors and metastatic lesions. Only a small number of small-molecule radiolabelled compounds are routinely employed in therapy mostly for pain palliation of metastatic bone cancer. There exist very few examples of radionuclides administered under a simple ionic form; the most widely employed being I-131 injected as iodide salt for the treatment of thyroid cancer. Strontium-89 is employed as Sn2+ ion for treating metastatic bone cancer and, recently, the alpha-emitting 223Ra as Ra2+ ion has been approved for the same indication.
The currently used therapeutic agents in nuclear medicine continue to pose vexing medical challenges mainly due to the limited uptake of radiocompound within tumor sites. This limited accumulation accounts for the fact that current beta-emitting therapeutic nuclear medicine agents have failed to deliver optimum therapeutic payloads at tumor sites. Actually, no other radiolabelled therapeutic agent has been capable to get close to the remarkably high target accumulation that was demonstrated by the long-lasting radionuclide I-131 in thyroid cancer. This means that metastases of several different types of aggressive cancers cannot be controlled, thus resulting in propagation of cancers to various other organs including bone, making it difficult to treat cancer patients. These challenges have resulted in minimal or no improvement in the quality of life for cancer patients.
Therefore, new delivery modalities that result in (i) effective delivery of therapeutic probes with optimum payloads, site specifically at the tumor sites, with minimal/tolerable systemic toxicity, and (ii) higher tumor retention, would bring about a clinically measurable shift in the way cancers are diagnosed and treated. Such oncological advances in targeted delivery of radioactive therapeutic probes would provide significant benefits to patient population worldwide.
The Role of Nanotechnogy
Nanotechnology has the potential to bring about a paradigm shift in the early detection and therapy of various forms of human cancers because radioactive nanoparticles of optimum sizes for penetration across tumor cell membranes can be engineered through a myriad of interdisciplinary approaches, involving teams of experts from nuclear medicine, materials sciences, physics, chemistry, tumor biology and oncologists. In particular, intervention of nanotechnology in nuclear medicine is poised to offer tremendous benefits in site-specific delivery of both diagnostic and therapeutic probes site specifically at tumor sites. This is possible because gamma and beta emitting isotopes can be converted into their corresponding nanoparticles. The sizes of diagnostic and therapeutic probes can be engineered to be within the 10-50 nm range so that they can penetrate tumor cells (which are 5-10 microns in size) to provide optimum diagnostic and therapeutic payloads for efficient diagnostic imaging and therapy.
Radiation induced production of polymeric nanoparticles using both the natural and synthetic polymers and proteins in combination with theranostic radioactive Au-198/199 (and other beta and gamma emitting radionuclides of Re, Sm, Rh etc.) would afford nanoceuticals within the 30-50 nm range. This size range would allow facile penetration of diagnostic and therapeutic payloads across tumor vasculature to achieve (i) effective delivery of optimum diagnostic/therapeutic payloads accompanied by minimal/tolerable systemic toxicity, and (ii) higher tumor retention using homogeneously dispersed diagnostic/therapy agents. Therefore, the overall approach which encompasses application of nanoparticulate radioactive probes in combination with polymeric nanomaterials has a realistic potential to generate the next generation of tumor specific theranostic nanoceuticals and minimize/eliminate delivery and tumor accumulation problems associated with the existing traditional nuclear medicine agents.
In this context, nanostructured antibodies when tagged with nanostructured diagnostic/therapeutic probes may also offer significant benefits over conventional radio-immunotherapy, because nanoparticulates can penetrate tumor vasculature and being retained by the tumor mass more efficiently than traditional antibody labeled radiopharmaceuticals.
Research Already in Progress in Member States
Within the framework of successfully completed CRP „Nanoscale Radiation Engineering of Advanced Materials for Potential Biomedical Applications” considerable progress has been made in the Member States in synthesizing polymer nanoparticles using radiation technique. These new nanomaterials include, among others, protein nanoparticles, nanogels of various physical and chemical properties, as well as nanoparticles based on polysaccharides (Argentina, Brazil, China, Egypt, Hungary, India, Italy, Korea, Malaysia, Poland, Serbia, Thailand and Turkey). These approaches were aimed at precise control of the structure, size, shape and functionality of the nano-scale products. In some cases, procedures were developed for preparing “hybrid” products, e.g., where the surfaces of nanoparticles and nanogels were decorated with functional polymers and biomolecules. It will be very valuable to build up on this accumulated knowledge and experience for creating new products where radiation-engineered nanoparticles are the basis of new generation of diagnostic and therapeutic systems for use in nuclear medicine.
A number of methods can be used to generate instructive matrices to be employed in tissue engineering. Among them, the application of radiation technology for formation and modification of surfaces and matrices has remarkable advantages such as: initiation of low temperature reactions, absence of harmful initiators, high penetration through the bulk materials and curing of different types polymeric materials (by polymerization, grafting and crosslinking). Additionally, radiation synthesized surfaces and scaffolds might simultaneously be modified and sterilized. Radiation sterilization is a well-established technology, it is a reliable and effective process used industrially for nearly 60 years. Medical devices, raw materials for pharmaceuticals, biomaterials, tissue allografts, and cosmetics among other products are routinely sterilized by ionizing radiation.
CRP Overall Objective
To exploit the unique properties of materials at the nanometer scale for developing nanocarriers of radioactivity capable of selectively targeting and penetrating cancerous cells.
Specific Research Objective
Specifically, participating institutions will investigate and optimize the preparation on instructive surfaces and scaffolds and their sterilization byradiation, to study the cell- scaffold-matrix interactions, as well as the effectiveness of combining biological and non-biological materials on regeneration/repair.
Expected Research Outputs
Technical guidelines, methods and protocols for synthesizing instructive surfaces and scaffolds by radiation methods and their sterilization, data on the cell-cell-matrix-scaffold interaction, as well as on the effectiveness of combined biological and non-biological materials on regeneration-repair are expected. Moreover, a multidisciplinary network of researchers and end-users is expected to be established.
Expected Research Outcomes
MS will have enhanced capability to engineer and use instructive scaffolds and surfaces for improved wound healing/repair/regeneration and reconstruction.