Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewThe role of recent nanotechnology in enhancing the efficacy of radiation therapy
Introduction
Radiation therapy has been used in cancer therapy for more than a century and is one of the most commonly used non-surgical interventions in tumor treatment. The initial efforts to apply external radiation therapy in patients have undergone radical improvements in the last decades, resulting in combined modality approaches, including radiochemotherapy (RCT) [1]. Despite recent advances in radiation oncology, however, treatment response and survival vary considerably between individual patients. These differences are most probably caused by a variation in intrinsic tumor cell resistance to radiation and/or chemotherapy that may originate from a different genetic background or protein expression, either already existent in the patient genome (in the form of polymorphisms) and/or newly acquired in malignant cells during carcinogenesis [2]. Further improvement of radiation therapy effectiveness can be accomplished by radiation sensitizers. Radiation sensitizers (or radiosensitizers) are usually chemical or pharmacologic agents that increase the lethal effects of radiation if administered in conjunction with it [3]. An important prerequisite for a radiation sensitizer is that it exerts a differential effect between normal tissues and tumors, i.e. it should increase the sensitivity of tumors more than that of healthy tissue [3]. For this purpose, a variety of approaches including recent molecular targeted therapies have been developed [4]. These can either enhance radiation response or counteract tumor cell radiation therapy resistance. Some targeted therapies have already made their way into the clinic but more refinements should be made, for example by improving their stability and tumor cell specificity. One way of improving tumor targeting is by applying highly selective drug delivery systems, such as nanocarriers (NCs), nanoparticles (NPs) or liposomes [5]. These NCs or NPs are ranging in size between 1 and 1000 nm and vary in their mechanical and/or physicochemical characteristics. Some of them can overcome physiological barriers such as endothelial cell layers and the blood brain barrier (BBB) [6]. In addition to those that serve for delivery of therapeutic agents, NPs exist that can directly interact with ionizing radiation (graphically summarized in Fig. 1) and thereby increase cellular radiation sensitivity. Such NPs are usually made of elements with a high atomic number (high-Z NPs) and have high potential for clinical use in line with their suitability as drug delivery systems and imaging enhancers.
A number of NCs for anti-cancer therapy entered the market between 1990 and the early years of the 21st century [5]. For cytostatic agents, nanotechnology has primarily been used to improve the toxicity profile and to overcome poor aqueous drug solubility and chemical stability issue thus improving pharmacokinetic and pharmacodynamic drug profiles and enhancing the therapeutic index [7]. In 2005 for example, Abraxane®, the first generation nanoparticle formulation of the chemotherapeutic drug paclitaxel has been approved for breast cancer treatment by the Food and Drug Administration of the United States of America (US-FDA) [5].
For other sensitive compounds such as nucleic acids, proteins or peptides the protection of the active pharmaceutical ingredient (API) had major impact on therapeutic efficacy as these molecules undergo rapid enzymatic degradation in human blood [8]. The half-lives of these substances could be increased significantly by nanoencapsulation into a protective shell.
By taking advantage of the enhanced permeability and retention (EPR) effect [9], [10], NCs can accumulate preferentially in tumor tissues. This passive extravasation of macromolecules into the tumor interstitial fluid (TIF) is the result of vascular endothelium lesions in solid tumors and the absence of lymphatic drainage assuring clearance of colloids from the intersitium [11]. In recent years, the existence and the effectiveness of EPR effect for tumor targeting have been subject of a controversial discussion. The rising TIF pressure and diversity of cancer diseases are major obstacles to this mechanism. Besides these aspects, biodistribution into other tissues is limiting the availability of nanoparticulate drug delivery systems in the tumor. After intravenous administration of the carrier, a number of accumulation mechanisms occur. NPs smaller than 25 nm effectively penetrate non-fenestrated endothelium while larger particles rapidly accumulate in the liver due to the fenestration of blood vessels with a pore size between 100 and 175 nm [12]. Prolonged circulation time has been reported for particles of a size between 150 and 300 nm [13]. Extravasation due to the EPR effect takes place more effectively at prolonged circulation times [10]. For NPs between 50 nm and the micrometer range, however, the greatest fraction accumulates in the liver. Over the years, the importance of the EPR effect for cancer therapy has been challenged as only minor effects were observed in clinical trials, in contrast to moderate increases in tumor accumulation of some nanoencapsulated chemotherapeutic drugs in animals.
A variety of NCs/NPs have recently been synthesized that took advantage of the outstanding potential of drug delivery in therapy and diagnosis of cancer. Some of them were modified on their surfaces with targeting ligands such as antibodies or other molecules in order to improve the pharmacokinetic profile of a compound and selectivity for cancer tissues. They have been extensively reviewed (for example in [7], [14], [15], [16], [17], [18], [19], [20]). Reviews focusing on the role of nanotechnology in radiation sensitization exist to a lesser extent [21], [22], [23], [24], [25]. In this review, we aim to provide information on the use of different classes of particles and nanotherapeutic strategies with an emphasis on surface modifications to improve radiation sensitization and their implications for clinical translation. Both in vitro (Table 1) and in vivo (Table 2) preclinical studies, as well as clinical trials in patients (Table 3) will be discussed.
Section snippets
Polymeric nanoparticles for tumor delivery of therapeutic agents
A variety of natural and synthetic polymeric NP formulations have been designed to enhance the effect and/or tumor delivery of radiation sensitizing agents, such as chemotherapeutic drugs, small molecule cancer drugs [26], [27], [28], [29] or nucleic acids [30], [31], [32]. In general, two different strategies have been applied to develop polymeric NPs. First, by decreasing the particle size of poorly soluble drugs to the nanosize range, dissolution rate [33] and (with limitations) second
High-Z nanoparticles
The first observations of dose enhancement by materials with high atomic (Z) numbers were made over 60 years ago [68]. It appeared that the tolerated dose of soft tissue elements in bone was lower than that of soft tissues in a different environment [68]. In the 1970s, enhanced chromosomal DNA damage was observed in lymphocytes of patients undergoing angiography with an iodine contrast agent [69]. Subsequently, the concept of dose enhancement by high-Z materials was tested by investigating the
Superparamagnetic nanoparticles (SPIONs)
An effective way of imaging and tumor targeting is the application of inorganic paramagnetic iron oxide NPs, or superparamagnetic nanoparticles (SPIONs) [39]. Superparamagnetism enables MRI aided visualization and highly specific guidance of SPIONs to the tumor tissue, via an external magnetic field, where they induce localized hyperthermia or deliver therapeutic agents resulting in radiation sensitization. A SPION is composed of magnetite (Fe3O4) or maghemite (Fe2O3) with appropriate coatings
Nanoparticles for photodynamic therapy
Photodynamic therapy (PDT) is a treatment option in which a combination of a photosensitizing drug and visible light results in cell death [122]. It is still considered to be an experimental therapy, but its status and value within modern clinical practice continues to grow [122]. Titanium dioxide (TiO2) has unique photocatalytic properties, excellent biocompatibility, high chemical stability and low toxicity [123] and has been studied in combination with radiotherapy for anti-cancer treatment.
Clinical trials on nanoparticles
The data of the preclinical research reported before suggest that treatment of patients with nanoparticles may result in a radiation- and/or chemosensitization of the tumor thus enhancing treatment response and patient survival. The first clinical trial registered by the U.S. National Institutes of Health (NIH) dates back to 2004 and tested Abraxane®, a nanoparticle formulation of the drug paclitaxel, as part of combined modality therapy in advanced breast cancer.
At the time of writing this
Conclusions
There is tremendous evidence that nanotechnology has potential to significantly enhance the therapeutic effect of current standard treatment modalities. During the last decades, a huge variety of nanoparticles have been developed and studied for their anti-cancer activity and ability to enhance the effect of radiation therapy. Of the existing studies, most have focused on nanoparticles consisting of high-Z material like gold or gadolinium. They have proven to be successful radiation sensitizers
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Acknowledgments
This manuscript was supported by a Joint Funding Grant within the German Cancer Consortium (DKTK), which is funded as one of the national German health centers by the Federal German Ministry of Education and Research (BMBF).
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