Applied Nanotechnology and Nanoscience in Orthopedic Oncology
Olga D. Savvidou, MD; Ioanna K. Bolia, MD, MSc; George D. Chloros, MD; Stavros D. Goumenos, MD; Vasileios I. Sakellariou, MD; Evanthia C. Galanis, MD; Panayiotis J. Papagelopoulos, MD,DSc
Nanomedicine is based on the fact that biological molecules behave similarly to nanomolecules, which have a size of less than 100 nm, and is now affecting most areas of orthopedics. In orthopedic oncology, most of the in vitro and in vivo studies have used osteosarcoma or Ewing sarcoma cell lineages. In this article, tumor imaging and treatment nanotechnology applications, including nanostructure delivery of chemotherapeutic agents, gene therapy, and the role of nano-selenium–coated implants, are outlined. Finally, the potential role of nanotechnology in addressing the challenges of drug and radiotherapy resistance is discussed. [Orthopedics.2016; 39(5):280–286.]
Nanotechnology refers to the process of making materials with a grain size of less than 100 nanometers (nm). Medical applications of nanotechnology—nanomedicine—are based on the fact that biological molecules, such as enzymes, proteins, and nucleic acids, behave like nanomaterials because their dimensions and properties are similar.1Moreover, their physical properties abide with the laws of quantum physics instead of classical mechanics.2
Typical nanomolecules in the musculoskeletal system include the collagen molecule (300 nm long and 1.5 nm in diameter), the myofilament structure (approximately 8 nm long), and other receptors and enzymes. Currently used orthopedic materials belong to the microscale level, where 1 mm is equal to 10−6 m. The nanoscale, where 1 nm is equal to 10−9 m, is therefore more biocompatible because the materials are able to interact and integrate more efficiently with the host tissue microenvironment. This article focuses on the applications of nanotechnology in the area of orthopedic oncology.
Osteosarcoma and Ewing Sarcoma
The majority of nanotechnology studies have used osteosarcoma or Ewing sarcoma cell lineages in their experiments. Osteosarcoma is a heterogeneous malignant bone cell tumor that has the ability to produce osteoid/immature bone. It may have a variable histological composition including bone, cartilage, fibrous tissue, or their combinations because of its pluripotential nature.3 Currently, limb salvage surgery and multidrug chemotherapy have replaced the older treatment regimen, which included amputation and monotherapy.3 Ewing sarcoma is a small round blue cell neoplasm without matrix production that most commonly affects children and young adults. In 85% to 90% of cases, Ewing sarcoma is the result of the production of the chimeric EWSYFli1 protein that activates transcription. This protein is encoded by the EWSYFli1 fusion oncogene, which is the product of the chromosomal translocation t(11;22)(q24;q12).4 Conventional treatment of Ewing sarcoma includes pre- as well as postoperative systemic chemotherapy, surgical removal of tumor, and local radiotherapy.
Although dramatic progress has been made in sarcoma therapy, significant challenges remain, including pharmacokinetic issues, decreased selectivity and increased cytotoxicity, drug-resistance phenom ena, and difficulty in accurately assessing the response to therapy. Nanotechnology can help overcome these challenges through the manufacture of special scaf folds/carriers to protect chemotherapeutic agents and transfer them selectively to targeted cells.
Diagnostic and Treatment Applications Using Nanotechnology
Nanotechnology can manufacture various nanoparticles, which can carry ligands. Those ligands can interact with specific molecules on the surface of targeted cells and therefore bind to them. By adding a contrast agent to the nanoparticle–ligand complexes (“loading” of the nanoparticle), accurate targeted imaging of tumors may be achieved at the cellular level.4 For instance, the mutated p15 gene is a tumor marker for osteosarcoma. In addition, there is a strong association between the presence of the mutated p15 gene and the propensity for lung metastasis.5 By adding a ligand that binds to cells that express the mutated p15 gene, via the above mechanism, early identification of metastasis or of the metastatic potential of the tumor may be achieved.4Superparamagnetic iron oxide (ie, metallic) nanoparticles or quantum dot nanocrystals have been studied in a similar fashion as contrast agents for targeted magnetic resonance imaging.6,7
Nanoparticles that can both absorb light and emit heat may be created. These nanoparticles will selectively permeate the tissue of interest and may be detected using laser technology. By delivering and detecting these particles, various intracellular processes may be assessed.8 Compared with conventional methods, which rely on histologic evaluation after surgical resection of the tumor, this may potentially offer higher accuracy in detecting the percent of viable tumor remaining.9 Typical nanostructures (assemblies of nanoparticles) used for the above purposes include hollow gold nanoshells, gold/gold sulfide nanoparticles, gold nanocages, carbon and titanium nanotubes, photothermal-based nanobubbles, polymeric nanoparticles, and copper-based nanocrystals.9
Nanotechnology applications have the potential to revolutionize the earlier detection of cancer, its metastases, or both and the ability to assess, in detail, the response after therapy.
Methods of Drug Delivery to Tumor Cells: Passive vs Active Targeting. Effectively treating sarcomas necessitates accurate delivery of an adequate intracellular concentration of drug to kill the cancer cells. There are two ways of transferring drugs to tumor sites: passive and active. Passive targeting (enhanced permeability and retention)10 takes advantage of the structural characteristics of the tumor vessels that make them permeable to the small (<100 nm) nanomolecules. However, there is also the potential for toxic accumulation to healthy tissues. Passive targeting works because, compared with healthy tissues, tumors have poor lymphatic drainage and therefore a much higher concentration of drug will be achieved inside them.4,11 Active targeting involves first creating a drug-loaded nanostructure. Then, this structure is coupled to a ligand that specifically binds to the surface of the targeted tumor cells. Finally, the entire complex is endocytosed and therefore the chemotherapeutic agent is driven directly into targeted cells.4 Examples of such surface ligands include monoclonal antibodies,10 mannose,12 folic acid,13 and ferritin.14
Examples of Drug-Loaded Nano-structures Against Tumor Cells. Lipid-based nanocarriers for the treatment of osteosarcoma, as described by González-Fernández et al,15 have a lower cost, better stability, and decreased toxicity and are more versatile than other types of nanocarriers. They can be loaded with both hydrophilic and hydrophobic molecules and therefore constitute an appealing option for drug delivery.16 There are three main categories of lipid-based nanocarriers3: solid lipid nanoparticles,17,18 nanostructured lipid carriers,19 and lipid–drug conjugate nanoparticles.20–23
Several research projects have used nanovectors to carry conventional anticancer agents such as doxorubicin and methotrexate for the treatment of osteosarcoma and Ewing sarcoma. The ultimate goal is to improve drug kinetics and therefore achieve superior therapeutic results.
Doxorubicin. Compared with conventional doxorubicin therapy, doxorubicin-loaded solid lipid nanoparticles were shown to improve the drug’s anticancer performance when used for a resistant ovarian carcinoma cell line (NCI/ADRRES).24 Mannose-coated nanoparticles may bind lectin surface molecules (galectin-3) overexpressed by osteosarcoma cells, resulting in precise delivery of chemotherapeutic drugs.25 In this way, doxorubicin delivery can lead to fewer systemic side effects and increased drug bioavailability.12 Doxorubicin-loaded PEGylated liposomes (Doxil; Janssen, Titusville, New Jersey) have received US Food and Drug Administration approval for the treatment of AIDS-related Kaposi’s sarcoma. Polyethylene glycol (PEG) is a synthetic hydrophilic polymer forming an hydration layer that facilitates accumulation of proteins on the nanoparticle’s surface, resulting in prolonged drug half-life.26 The cytotoxic effect of the above nanostructures was attributed to the high uptake of the complex as well as to the blockage of multidrug resistance protein 1.27Because osteosarcoma cells also express the folate receptor,28 this would be a potential treatment approach. In addition, the reduced folate carrier that is expressed on the surface of sensitive but not of resistant osteosarcoma cells serves as a means to actively transport methotrexate intracellularly.15 Regarding osteosarcoma lung metastases, a potential treatment could be based on nanostructured lipid carriers loaded with doxorubicin and a silencing RNA (siRNA) molecule against Bcl-2 and P-glycoprotein to overcome drug resistance. Delivery to the lungs has been achieved by adding a synthetic analog of luteinizing hormone–releasing hormone to this complex.29
Methotrexate and Newer Antifolates. Conventional chemotherapeutic treatment with methotrexate requires a high dosage and thus leads to increased toxicity. In two in vivo studies involving breast cancer cells, nanotechnology-produced solid lipid nanoparticles loaded with methotrexate showed improved gastrointestinal absorption30 and increased bioavailability, thus requiring lower dosages and therefore leading to decreased toxicity.30,31 Lipid nanoparticles can also be used to deliver the newer antifolate chemotherapeutic agents, including trimetrexate and pemetrexed, to osteosarcoma cells. Trimetrexate inhibits the enzyme dihydrofolate reductase, but its intracellular concentration is reduced by the action of multidrug resistance protein 1 as well as by its inability to be polyglutamylated for longer retention.32,33 The use of trimetrexate-loaded lipid nanoparticles may overcome these issues and improve the anticancer effect. Pemetrexed enters the cell via the membrane carrier and blocks the action of various folate-related enzymes (eg, thymidylate synthase, dihydrofolate reductase).34 Mutations of the transport protein make it unable to transfer the drug intracellularly. However, this can be overcome by encapsulation of pemetrexed in lipid nanoparticles, which may be used to transport the drug intracellularly independently of the mutated carrier.3
Etoposide. Compared with conventional treatment with etoposide, etoposide-loaded solid lipid nanoparticles showed superior ability to kill metastatic lung cancers in one study.35 Therefore, further research on this for primary osteosarcoma lung metastases is warranted. Osteosarcoma cells, especially in metastases, express CD44 receptors.36 The successful active targeting of these receptors in ovarian carcinoma37 may provide insights for the treatment of osteosarcoma.
Nanovehicles Interacting With Molecular Pathways. Receptors with tyrosine kinase activity are found in several sarcoma oncogenic pathways.38 For example, the insulin-like growth factor receptor 1 pathway is strongly associated with both osteosarcoma39,40 and Ewing sarcoma.41,42 In osteosarcoma, the polo-like kinase 1 inhibitor scytonemin induces apoptosis in a dose-dependent manner and the blockade of Mirk kinase is associated with tumor cell death. Nanovehicles that bind to ligands that interfere with the tyrosine kinase pathway, and therefore successfully induce apoptosis, have been studied in vitro.43,44 Other potential targets for osteosarcoma treatment at the molecular level include vascular endothelial growth factor and its receptor, the phosphatidylinositol-3 kinase pathway, platelet-derived growth factor receptor, the liposomal muramyl tripeptide phosphatidylethanolamine, hypoxia-inducible factor 1, human epidermal growth factor receptor 2, and insulin-like growth factor receptor 1.3
Hydroxyapatite Nanoparticles in Different Osteosarcoma Cell Lines. Hydroxyapatite nanoparticles with various nanosphere sizes have been studied regarding their cytotoxicity to different osteosarcoma cell lines. Both small and large hydroxyapatite nanoparticles have been shown to kill osteosarcoma U2OS cells, with the smaller being more toxic than the larger.45 In contrast, a similar experiment46 with osteosarcoma MG-63 cells found that large hydroxyapatite nanoparticles were the best inhibitor of these cells compared with small hydroxyapatite nanoparticles. These diverging results were mainly attributed to phenotypic and genetic diversity between the U2OS and the MG-63 cell lines.46 All of the hydroxyapatite nanoparticles were morphologically similar.45,46 In addition, the apoptotic mechanism of both small and large hydroxyapatite nanoparticles involved the intrinsic pathway with the activation of procaspase-9 to caspase-9 secondary to the release of calcium and phosphate in the cell cytoplasm.46
Gene Therapy Using Nanotechnology. Another approach to treat or prevent malignancy is to inhibit the differentiation process of cancer-initiating cells toward tumor cells or to knock down specific genes that contribute to the development of a malignant phenotype. Nanotechnology, by offering vehicles to transport RNA/DNA molecules or other factors to affect the gene expression process of tumor cells, could potentially provide significant opportunities to achieve this goal.4 For example, CD133 is a molecular marker for osteosarcoma47 and Ewing sarcoma48 cancer-initiating cells. Nanostructures can be loaded with specific molecules to inhibit this marker. Moreover, alteration of the signaling cascade that drives a primitive cell to express malignant characteristics and also epigenetic modification of gene expression have been shown to be effective ways of preventing tumorigenesis.49
Because Ewing sarcoma is the result of a fusion oncogene (in most cases, EWSYFli1), an siRNA molecule may be used to knock down its expression. Among the various ways to deliver an siRNA molecule is the production of the preferred sequence and its direct introduction into the tumor cell.50–52 However, this is difficult because of the susceptibility of the siRNA molecule to degradation during its delivery as well as the aforementioned problems of blocked cell penetration.52,53 Thus, lipid nanocarriers were thought to be a good solution. One study54 used noncationic polyisobutylcyanoacrylate nanocapsules as a “safe” in vivo delivery system for siRNA molecules targeted at the Ewing sarcoma oncogene. Doing so avoided their degradation by nucleases.55 In models involving mice, two protocols were used to compare the cytotoxic effect of free vs nanoencapsulated siRNA molecules on Ewing sarcoma tumor cells.54 The latter were found to be significantly superior for inhibiting tumor growth. The same siRNA molecule, apart from the inhibition of the fusion oncogene, also blocked the expression of the EWS gene, perhaps because the EWS and EWSYFli1 proteins form heterodimers.56 Thus, the final tumor inhibition could be the result of the synergistic effect of both processes.54
Similar applications using antisense DNA oligonucleotides against specific genes can be employed. Maksimenko et al57 showed that nanocapsules or nanospheres were useful for delivering antisense DNA oligonucleotides to Ewing sarcoma tumor cells in mice and effectively knocked down the expression of the EWSYFli1 oncogene.
Mesoporous silica nanoparticles possess distinct structural and morphological characteristics that make them excellent candidates to be nanocarriers for gene therapy,58,59 apart from their potential use in drug delivery systems60 or as contrast agents for magnetic resonance imaging to improve tumor detection applications.61,62These characteristics include the ability to manipulate their morphology and dimensions, their increased surface area, and their excellent biocompatibility and biodegradability properties.63 Pore size has been shown to play a crucial role regarding what molecules the mesoporous silica nanoparticles are able to carry. Structures with pore sizes of less than 3 nm can host siRNA64–66 sequences, but are only partially protected (external surface). Structures with larger pores offer better protective/coating properties not only for genetic molecules, which are now resistant to the action of nucleases,37,67 but also for proteins and enzymes.37
Role of Nano-selenium in Orthopedic Oncology. Selenium metalloid68 is an antioxidant natural trace element.69,70 During metabolic and oxidative burst cell processes, reactive oxygen species are produced that are toxic to the cells (oxidative stress). Selenium acts as a cofactor in chemical reactions that neutralize reactive oxygen species and has antibacterial71,72 and anticancer73–75 properties. In several in vitro studies, coating conventional orthopedic materials (eg, bone implants) with nanotechnology-manufactured selenium (nano-selenium) has been shown to induce apoptosis in osteosarcoma cells while promoting healthy bone properties. Tran et al75 manufactured an “anticancer” nano-selenium–coated titanium implant that simultaneously promoted healthy bone cell functions (alkaline phosphatase activity, adhesion, proliferation, and calcium deposition) and inhibited cancerous bone cell functions. Wang et al76 showed that selenium-coated hydroxyapatite nanoparticles were more cytotoxic than non– selenium-coated hydroxyapatite nanoparticles for human osteosarcoma cell lines (MG-63). The mechanism of apoptosis in these cells includes the activation of caspase-9 (ie, the intrinsic apoptotic pathway) after the generation of reactive oxygen species and the release of cytochrome c from the mitochondria to the cell cytoplasm.77–81 Stolzoff et al82 manufactured poly-L-lactic acid implants coated with selenium nanoparticles and showed that they decreased the survival of osteosarcoma cells while concomitantly increasing the function of healthy osteoblasts (ie, increased alkaline phosphatase activity).
Overcoming Drug and Radiotherapy Resistance
Drug resistance is a major problem when treating patients who have osteosarcoma. Resistant cells usually overexpress P-glycoprotein 1 (also known as multidrug resistance protein 1), transporting the chemotherapeutic drug out of the cell and thereby decreasing its intracellular concentration. The existing polymorphisms83 in this membrane adenosine triphosphate–dependent transporter, in combination with the expression of additional proteins such as metallothionein, heat shock proteins, thymidylate synthase, dihydrofolate reductase, and O6-alkylguanine DNA alkyltransferase84 within the tumor cell, make the development of regimens to overcome drug resistance extremely challenging. Nanotechnology can produce vehicles to transfer anticancer agents or siRNA molecules specifically to resistant tumor cells to improve their sensitivity to drugs. Using an siRNA sequence to knock down P-glycoprotein may be an effective strategy for overcoming drug resistance.4 To achieve these goals, such carriers must be able to evade the immune system response and, most importantly, protect the delivered siRNA from degradation processes, including the action of nucleases and the clearance by the cells of the reticuloendothelial system.85 Also, the carriers must be manipulated and capable of being endocytosed specifically by the drug-resistant cells to effectively release their content into the cell cytoplasm.85 Nano-carriers with these properties include liposomes, cationic polymers, inorganic carriers (porous silicon nanoparticles, gold nanoparticles, and apatite nanoparticles), beta-cyclodextrin nanocarriers, and nanogels.85
A study conducted in 2009 used in vitro polymeric nanoparticles loaded with doxorubicin to evade the P-glycoprotein transporter in drug-resistant osteosarcoma cell lines and increase the intracellular drug concentration.86 The accumulation of doxorubicin within these cells, transported via this nanostructure vehicle, was comparable to that in the drug-sensitive cell lines. The same authors87 used dextran-based nanoparticles after lipid modification processing to deliver siRNA molecules to osteosarcoma cells expressing multidrug resistance protein 1 (ABCB1). They reported successful downregulation of P-glycoprotein expression together with resensitization of such cells for doxorubicin.
Radiotherapy resistance is positively correlated with the increased proportion of cancer-initiating cells.88,89Resistance may also arise from radiation recovery processes that occur during fractionated radiotherapy, by repopulation of tumor cells in the intervals between radiation treatments.90,91 Hydrogenated nanodiamonds may be used to overcome this problem. They are able to produce additional reactive oxygen species at the tumor site, apart from those already produced by conventional radiotherapy, and thus increase the sensitivity of cancer cells to radiation. Such studies have been conducted with cell lines other than those of orthopedic tumors.92
Nanotechnology exploits the unique advantage of direct interaction with cells at the molecular level. A new horizon of improved accuracy in diagnosis and treatment via precise contrast agents and delivery of chemotherapeutic drugs is emerging. Nanotechnology-manufactured orthopedic implants with improved anti-cancer properties have been developed in vitro (eg, nano-selenium). The challenges of drug and radiotherapy resistance may be better met through nanotechnology-based applications. Further research regarding orthopedic applications is warranted in this new era of nanotechnology.
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