Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer☆
Introduction
Cancer has been one of the major social and health concerns for the last ten decades, albeit the milestones achieved in both diagnosis and treatment procedures. The use of nuclear medicine applications in oncology is of a particular importance as a rapidly developing therapeutic and diagnostic multimodality.
The investigation of novel tumor-targeting radiopharmaceuticals is currently one of the potential fields of interest for researchers for both tumor scintigraphy and/or treatment. Radiopharmaceuticals are dosage forms consisting of two components, a carrier and a trace amount of a radionuclide with a defined radiation type(s). Therefore, the efficacy of a radiopharmaceutical is determined by these two components. In tumor radiotherapy, the therapeutic effect is due to the tumoral absorption of alpha (α) or beta (β) radiation energy emitted by the radionuclide. The ideal radiopharmaceutical should convey the radioactive nuclide quantitatively to the tumor tissue, with no radiation reaching the normal tissues. In this context, the recent progress in pharmaceutical nanotechnology field has been efficiently exploited in developing promising approaches based on the design of novel nano- and microcarriers, which function to improve the outcome of radiotherapy and the quality of diagnosis [1].
It is well established that nanomedicine is currently attracting a worldwide interest of researchers who aim to dedicate this technology to develop novel approaches in cancer imaging, molecular diagnosis and targeted therapy [2]. Anticancer drug delivery systems are of the most investigated research areas in nanomedicine. Numerous investigations have shown that incorporating anticancer agents in nanoparticulate or microparticulate carriers would provide a useful means for controlling the tissular and cellular distribution profiles of these agents. The rationale behind these approaches is to combine a drug controlled-release fashion with a targeted delivery in order to provide more efficient and less harmful solutions, thus, surmounting the limitations often encountered in conventional chemotherapy [3], [4].
Among these different systems, particulate nanoscale carriers (i.e. liposomes, nanoparticles) have gained most of the researchers' attention due to their potential qualities. They are classified into three generations. The first generation of nanocarriers is known for its rapid clearance from the blood stream and high uptake by the macrophages of the reticuloendothelial system (RES) (e.g. Kupffer cells of the liver) due to the opsinisation processes occurring at the surface of these carriers following an intravenous administration. Therefore, many research papers demonstrated practically the possibility to beneficiate from such biodistribution profile as a passive targeting method for the treatment of hepatic cancers [5], [6].
To reduce their toxicity, overcome the RES capture and prolong their blood circulation time, the nanocarriers surface properties have been modified by covalently binding hydrophilic poly(ethylene glycol) (PEG) chains leading to the emergence of the second generation; PEGylated nanocarriers [7], [8]. This generation is exemplified in the work of Brigger et al. who reported an enhancement of the brain tumor uptake of PEGylated nanoparticles compared with conventional nanocarriers [9], [10]. A further development on the nanocarriers was carried out by binding specific recognition ligands (e.g. antibodies, folic acid) to their surface [11], [12]. This allows an active rather than passive targeting of the cancerous cells framing the third generation of nanocarriers.
Targeted vectors typically have an architecture comprised of a building polymeric or lipidic matrix, a targeting moiety being any molecule that selectively recognizes and binds to ligands on target cells, and a loaded diagnostic or therapeutic agent. Based on this general assembly, several types of carriers have been elaborated in the last few decades. These carriers include, among others, submicronic systems like liposomes, nanoparticles, micelles and dendrimers, micoparticulate systems (microparticles) and lastly hydrogels (Fig. 1). These different vectors have shown to be auspicious means in the delivery of anticancer drugs [13], [14], [15], [16], [17], [18]. Therefore, depending on their interesting characteristics which confer an improved intra-tumoral delivery for the therapeutic molecules, all of these vectors were investigated for the delivery of radionuclides for both cancer nuclear imaging and radiotherapy.
In nuclear imaging, radiolabelled carriers can be applied as non-invasive diagnostic Emfietzoglouagents to provide both functional and structural data about the malignant tissues and their surroundings. The different nuclear medicine imaging modalities include single photon emission-computed tomography (SPE/CT), positron emission tomography (PET) and positron emission tomography-computed tomography (PET/CT). These imaging techniques are all of great clinical value for earlier recognition of the presence and the extent of malignancy based on the fact that biochemical changes generally precede anatomical changes [19]. Cancer radiotherapy, in turn, involves external and internal radiotherapy routes. In this framework, the radiolabelled nano- and microcarriers are designed for internal radiotherapy via intra-tumoral or systemic administration routes in the aim of obtaining a localised radiation in the interior of the tumor area avoiding radiation dissemination within the body [1]. In this paper, we review the utilisations, limitations and advantages of the different radiopharmaceutical nano- and microcarriers, including liposomes, microparticles, nanoparticles, micelles, dendrimers and hydrogels, for tumor imaging and radiotherapy.
Section snippets
Radionuclides for nuclear imaging
Radionuclide imaging is commonly devised into two general modalities; single photon emission computed tomography (SPECT) and positron emission tomography (PET). Generally, typical imaging studies include dynamic or static imaging and in vivo function tests. Dynamic imaging provides clinicians with necessary data about biological turnover of radioisotopes in different body compartments and organs. Single-photon radionuclides emit gamma (γ) rays in the energy range of approximately 75 to 360 keV
Liposomes
Liposomes are self-assembling vesicles with an inner aqueous compartment surrounded by a phospholipidic bilayer [39]. Liposomes can encompass hydrophilic agents in the inner aqueous compartment or/and lipophilic agents in the outer lipid membrane. Accordingly, different modalities to encapsulate radionuclides in liposomes or to radiolabel them can be applied in consistence with the solubility of the utilised radionuclide or radionuclide conjugate [40], [41].
Conclusion
Great steps are being taken every day in pharmaceutical nanotechnology towards changing the scale and methods of radioisotope delivery for a better future of cancer radiotherapy and imaging. Different radiolabelled nano- and microcarriers have been elaborated for passive or active targeting of tumors with promising results in spite of the fact that not all these targeting mechanisms are actually clearly understood. Many of these carriers have been successfully applied in both preclinical and
Acknowledgement
The author aknowledge the companies: Advanced Aceelerator Applications and Cerma for the financial help and the scientific collaboration through the research grant Eureka and the project INBARCA.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery Systems for the Targeted Radiotherapy of Cancer”.