Fungus-based nanoparticles: inspiration from nature for cancer therapy

Abstract

NanomedicineVol. 8, No. 3 EditorialFree AccessFungus-based nanoparticles: inspiration from nature for cancer therapyMingjun ZhangMingjun ZhangDepartment of Mechanical, Aerospace & Biomedical Engineering, University of Tennessee, 408 Dougherty Engineering Building, 1512 Middle Drive Knoxville, TN 37996, USA. Search for more papers by this authorEmail the corresponding author at mjzhang@utk.eduPublished Online:11 Mar 2013https://doi.org/10.2217/nnm.13.13AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cancer therapyfungus-based nanoparticleimmunochemotherapynanoparticlenaturally occurring nanoparticleNature has long been an important source of inspiration for engineering design. Through evolution, nature produces nearly endless biological diversity. Naturally occurring nanoparticles (NONPs) have drawn increasing interest in nanomedicine owing to their unique biocompatibility, biodegradability and immunogenicity. The majority studies of NONPs have focused on higher organisms. A carnivorous fungus was recently discovered to produce nanoparticles showing promise for cancer immunochemotherapy, which is an interesting case study for bioinspired nanomedicine.Underlying principles of biological systems in nature, especially those at the nanoscale, have been, and will continue to be, an important source of inspiration for nanomedicine, not only in terms of disease understanding, but also disease prevention, diagnosis and treatment. This article offers the author’s personal perspective on a class of NONPs produced by a carnivorous fungus – Arthrobotrys oligospora. The nanoparticles have demonstrated unique properties for cancer immunochemotherapy. The goal of this discussion is not to provide a final solution for this challenging disease, but rather to offer inspiration from biological systems in nature for cancer nanomedicine. By understanding how these nanoparticles are formed within this natural system and how they function, one may inspire bioinspired nanoparticles for cancer therapy.Biological systems can produce many different types of naturally occurring nanocomponents, including nanoparticles, nanofibers and nanotubes, among others [1–4]. NONPs can be easily found in air, soil, water, mineral composites and many biological systems. Some NONPs are produced by biological systems to carry out specific functions [3]. Many others are simply generated from biological systems as a result of the physical or chemical interactions of biological systems within their natural environments. It remains unclear whether there are NONPs produced specifically by biological systems for fighting diseases. However, nanofibers and nanoparticles have been found to contribute to the beneficial effects of a traditional Chinese medicine that has been used for over 130 years for wound healing [5].There is a growing interest in using NONPs in nanomedicine owing to their unique biocompatibility, biodegradability and immunogenicity. The majority of NONPs are found to have minimal or no cytotoxicity against humans. NONPs with diverse chemical properties could potentially introduce various methods for disease treatment, either directly or through further modification.In the field of medicine, particularly oncology, nanoparticles have shown promise in targeted drug delivery. Their small size permits them to easily cross cell membranes, which is an essential requirement for most cancer therapies. Although much research has been conducted in order to fabricate different types of nanoparticles for applications in medicine, NONPs have not been proposed as potential cancer therapeutic agents. The majority of studies on NONPs have focused on higher organisms; however, given the Earth’s rich biological diversity, it is reasonable to believe that NONPs of various forms and functions may be produced from a variety of organisms, ranging from microbes to metazoans. These NONPs may offer great diversity with numerous potential effects for advanced disease treatment.Cancer is a multifactorial syndrome. Consequently, the use of combination therapy utilizing nanoparticle-based drugs in conjunction with biological medical components has demonstrated promising clinical efficacy and has drawn increasing interest resulting in a biomaterial. Although several nanoparticle-based delivery systems have been proposed to simultaneously deliver chemical drugs and immune stimulants for cancer immunochemotherapy [6], few of these engineered nanoparticles have immunostimulatory activity themselves [7]. This is another unique property that the proposed fungus-based nanoparticles may introduce to combination cancer therapy.Fungus-based nanoparticlesA. oligospora, a nematophagous fungus, has multiple lifestyles. It can change from a saprophyte into its predatory stage in the presence of nematodes or proteinaceous substances, characterized by the formation of 3D adhesive-trapping networks that can trap nematodes for subsequent digestion [8]. A. oligospora is not only a nematode pathogen, but also a saprophyte, a pathogen of other fungi and a colonizer of plant roots. The carnivorous fungi can be easily found in diverse soil environments, including heavy metal-polluted soils and decaying wood. Owing to its broad adaptability and flexible lifestyle, the fungus has been previously used for the control of parasitic nematodes in both plants and animals [9,10]. Several biopolymers isolated from these 3D-trapping networks have also been reported to be involved in the adhesion process [11].Through our recent study, we found that A. oligospora could be used to fabricate nanoparticles [1]. A sitting-drop culture system has been developed to produce large amounts of organic nanoparticles from the fungus. The culture system can also be used to observe fungal growth, as well as secreted and surface-bound nanoparticles by scanning electron microscopy and atomic force microscopy without any disturbance from agar components present in solid media. Further analyses reveal that there is approximately 28 µg of glycosaminoglycan and 550 µg of protein per milligram of the fungus-based nanoparticles.In the literature, some glycosaminoglycans, such as heparin, heparan sulfate and chondroitin sulfate, have been reported as potential cancer therapeutics, inhibiting tumor cell adhesion, migration, growth and invasion in vitro[12]. Other proteoglycans formed by covalently attaching glycosaminoglycans to core proteins, such as decorin, are believed to be effective therapeutics that could reduce primary tumor growth by up to 70% and eliminated metastases in an orthotopic mammary carcinoma model [13]. Inspired by these studies, we tested the potential immunostimulatory and cytotoxic effects of the fungus-based nanoparticles in vitro. The nanoparticles were found to induce TNF-α, IL-6 and G-CSF secretion in RAW 264.7 mouse macrophages. Examination of the cytotoxicity from the NONPs against RAW 264.7 macrophages by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that there were no cytotoxic effects. The nanoparticles themselves were found to be slightly cytotoxic to mouse melanoma B16BL6 and human lung cancer A549 cells. This implies that the nanoparticles may be a potential candidate for tumor therapy, especially when conjugated with anti-tumor drugs.Besides the macrophage-activating effects, the fungus-based nanoparticles have been observed to enhance the proliferation of RAW 264.7 macrophages in a dose-dependent manner at all concentrations examined during a 24 h incubation period. Although it is still not clear if the proliferation effect was attributed to the TNF-α secretion, the increased proliferation of the macrophages will aid in the modulation of macrophage immune function in vivo[14]. Therefore, the fungus-based nanoparticles may serve as a bioactive drug carrier that can exert anti-tumor effects through a synergistic combination of immunostimulation, direct tumor cell killing and targeted drug delivery.DiscussionOne concern for using fungus-based nanoparticles as a drug delivery vehicle is the potential immunogenicity in normal tissues. We do not expect significant immunogenicity for the fungus-based nanoparticles, as they mainly consist of polysaccharide and proteins [1], which are similar to the compositions of polysaccharide-K (a protein-bound polysaccharide) isolated from a fungus (mushroom). Polysaccharide-K has been used as an anti-tumor drug in Japanese clinics for approximately 30 years, owing to its immunostimulatory and anti-tumor activities [15]. So far, no obvious immunogenicity has been reported in polysaccharide-K-treated patients [15,16].The use of the fungus-based nanoparticles represents a new approach in drug delivery for cancer therapy. The proposed sitting-drop culture method can be used to produce high-quality nanoparticles from the fungus, instead of fabricating drug delivery systems using synthetic macromolecules and organic solvents. In addition, the fungus-based nanoparticles have demonstrated both immunostimulatory and anti-tumor properties. These properties are promising for cancer immunochemotherapy. Few engineered biomaterials have been proposed as immunostimulants. The fungus-based nanoparticles may open up a new avenue for cancer immunochemotherapy, as no additional immunostimulants are needed in the treatment. The development of NONPs, which can function as a cytotoxic agent, drug delivery system and immunostimulatory agent, could remarkably simplify the process of nanoparticle fabrication for therapeutic applications in cancer immunochemotherapy.ConclusionThis study marks the initial stages of using fungus-based nanoparticles for cancer therapy and demonstrates the importance of looking to nature for innovation in nanomedicine. Additionally, it may open up a new avenue for controlling the synthesis of organic nanoparticles using synthetic biology inspired from studying the naturally occurring biological process. Nevertheless, further studies are needed before these nanoparticles can be utilized in clinical applications.Nanotechnology, through biology, offers plenty of opportunities for nanomedicine. Bioinspired nanotechnology will seemingly provide many promising opportunities, although it is still in the early stages of its development. The keys for bioinspired nanotechnology lie in the ability to understand the underlying principles of biological systems and extract the essential biological functions or properties that can be used for inspiration in engineering design. In our laboratory, we employ a three-step approach for bioinspired nanotechnology, including the elucidation of unique functions and properties of biological systems, the identification and extraction of working principles at the nanoscale, and the enhancement, as well as integration, of these principles for the synergistic development of nanomedicine. This approach has been demonstrated to be promising for our work on ivy nanoparticles for sunscreen [17], sundew nanoparticles for tissue engineering [18] and bioinspired robotics [19,20]. This work requires the significant integration of engineering principles with biology. On one hand, it may generate new insights for biological systems. On the other hand, by providing an engineering approach to understanding biology, it may offer significant advantages with practical implementations in nanomedicine. This work may not only require the creative integration of advanced nanoinstrumentation with engineering principles, but also a new type of bioinspired engineering practice that is fast emerging. Ultimately, mathematical modeling, analysis and systems theory could all work together with experimental approaches to contribute to the growth of future nanomedicine and nanobiosystems.Financial & competing interests disclosureThis research is partially sponsored by the US Army Research Office (W911NF-10–1–0114) and the National Science Foundation (CMMI: 1029953, CBET: 0965877). The author is grateful for the support. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Wang Y, Sun L, Yi S, Huang Y, Lenaghan CS, Zhang M. Naturally occurring nanoparticles from Arthrobotrys oligospora as a potential immunostimulatory and antitumor agent. Adv. Funct. Mater. doi:10.1002/adfm.201202619 (2012) (Epub ahead of print).Medline, Google Scholar2 Burris J, Lenaghan S, Zhang M, Stewart C. Nanoparticle biofabrication using English ivy (Hedera helix). J. Nanobiotechnol.10(1),41 (2012).Crossref, Medline, CAS, Google Scholar3 Zhang M, Liu M, Prest H, Fischer S. Nanoparticles secreted from ivy rootlets for surface climbing. Nano Lett.8(5),1277–1280 (2008).Crossref, Medline, CAS, Google Scholar4 Lenaghan SC, Zhang M. Real-time observation of the secretion of a nanocomposite adhesive from English ivy (Hedera helix). Plant Sci.183(0),206–211 (2012).Crossref, Medline, CAS, Google Scholar5 Lenaghan SC, Xia L, Zhang M. Identification of nanofibers in the Chinese herbal medicine: Yunnan Baiyao. J. Biomed. Nanotechnol.5(5),472–476 (2009).Crossref, Medline, CAS, Google Scholar6 Praetorius NP, Mandal TK. Engineered nanoparticles in cancer therapy. Recent Pat. Drug. Deliv. Formul.1(1),37–51 (2007).Crossref, Medline, CAS, Google Scholar7 Zolnik BS, Gonzalez-Fernandez A, Sadrieh N, Dobrovolskaia MA. Nanoparticles and the immune system. Endocrinology151(2),458–465 (2010).Crossref, Medline, CAS, Google Scholar8 Yang Y, Yang E, An Z, Liu X. Evolution of nematode-trapping cells of predatory fungi of the Orbiliaceae based on evidence from rRNA-encoding DNA and multiprotein sequences. Proc. Natl Acad. Sci. USA104(20),8379–8384 (2007).Crossref, Medline, CAS, Google Scholar9 Nordbringhertz B, Mattiasson B. Action of a nematode-trapping fungus shows lectin-mediated host–microorganism interaction. Nature281(5731),477–479 (1979).Crossref, CAS, Google Scholar10 Yang JK, Wang L, Ji XL et al. Genomic and proteomic analyses of the fungus Arthrobotrys oligospora provide insights into nematode-trap formation. PLoS Pathog.7(9),e1002179 (2011).Crossref, Medline, CAS, Google Scholar11 Tunlid A, Johansson T, Nordbringhertz B. Surface polymers of the nematode-trapping fungus Arthrobotrys oligospora. J. Gen. Microbiol.137,1231–1240 (1991).Crossref, Medline, CAS, Google Scholar12 Yip GW, Smollich M, Gotte M. Therapeutic value of glycosaminoglycans in cancer. Mol. Cancer Ther.5(9),2139–2148 (2006).Crossref, Medline, CAS, Google Scholar13 Reed CC, Waterhouse A, Kirby S et al. Decorin prevents metastatic spreading of breast cancer. Oncogene24(6),1104–1110 (2005).Crossref, Medline, CAS, Google Scholar14 Schepetkin IA, Quinn MT. Botanical polysaccharides: macrophage immunomodulation and therapeutic potential. Int. Immunopharmacol.6(3),317–333 (2006).Crossref, Medline, CAS, Google Scholar15 Maehara Y, Tsujitani S, Saeki H et al. Biological mechanism and clinical effect of protein-bound polysaccharide K (KRESTINA (®)): review of development and future perspectives. Surg. Today42(1),8–28 (2012).Crossref, Medline, CAS, Google Scholar16 Sun C, Rosendahl AH, Wang XD, Wu DQ, Andersson R. Polysaccharide-K (PSK) in cancer – old story, new possibilities? Curr. Med. Chem.19(5),757–762 (2012).Crossref, Medline, CAS, Google Scholar17 Xia L, Lenaghan S, Zhang M, Zhang Z, Li Q. Naturally occurring nanoparticles from English ivy: an alternative to metal-based nanoparticles for UV protection. J. Nanobiotechnol.8(1),12 (2010).Crossref, Medline, Google Scholar18 Zhang M, Lenaghan S, Xia L et al. Nanofibers and nanoparticles from the insect-capturing adhesive of the Sundew (Drosera) for cell attachment. J. Nanobiotechnol.8(1),20 (2010).Crossref, Medline, Google Scholar19 Lenaghan SC, Davis CA, Henson WR, Zhang Z, Zhang M. High-speed microscopic imaging of flagella motility and swimming in Giardia lamblia trophozoites. Proc. Natl Acad. Sci. USA108(34),E550–E558 (2011).Crossref, Medline, CAS, Google Scholar20 Xu Z, Lenaghan SC, Reese BE, Jia X, Zhang M. Experimental studies and dynamics modeling analysis of the swimming and diving of whirligig beetles (Coleoptera: Gyrinidae). PLoS Comput. Biol.8(11),e1002792 (2012).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 8, No. 3 Follow us on social media for the latest updates Metrics History Published online 11 March 2013 Published in print March 2013 Information© Future Medicine LtdKeywordscancer therapyfungus-based nanoparticleimmunochemotherapynanoparticlenaturally occurring nanoparticleFinancial & competing interests disclosureThis research is partially sponsored by the US Army Research Office (W911NF-10–1–0114) and the National Science Foundation (CMMI: 1029953, CBET: 0965877). The author is grateful for the support. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download