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Biosynthesized silver nanoparticles: a step forward for cancer theranostics? “…our group has designed and developed green synthesized silver nanoparticles that show multifunctional activities for biomedical applications using a nanomedicinal approach.” Keywords: biosynthesis • cancer theranostics • multifunctional activities • nanomedicine • novel treatment strategy • silver nanoparticles • SNP
Cancer: a global problem Cancer, a disease initiated by uncontrolled cell division in any part of the body, is a major public health problem globally, includ ing in developed countries, as a cause of mor bidity and mortality  . According to Global Cancer Control, approximately 12.7 million new cancer patients were diagnosed, with 7.6 million deaths, in 2008 and this is pre dicted to increase 21.4 million by 2030  . Conventional treatment strategies for cancer include surgery, radiation therapy, chemo therapy or combination of these. However, these strategies have several limitations including damaging healthy cells, nonspeci ficity, toxicity of anticancer drugs, poor bio availability, fast clearance and restrictions in the case of metastasis. According to the highlights published in May 2008 by BCC Research.com, the market value of global can cer therapeutics was US$47.3 billion in 2008 and expected to increase US$110.6 billion by 2013 with a compound annual growth rate of 12.6%  . Therefore, it is immediately necessary to establish an economically cheaper alterna tive treatment strategy for the development of cancer disease rather than the orthodox exist ing approaches. In this context, our group has designed and developed green synthe sized silver nanoparticles (SNPs) that show multifunctional activities for biomedical applications using a nanomedicinal approach. Nanomedicine approach for cancer Precisely engineered and fabricated nanoma terials can overcome the limitations found
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in conventional therapeutic and diagnostic agents. Recently, metal nanoparticles have been significantly used for the development of alternative theranostic strategies for can cer and other diseases, due to their unusual chemical, physical and electronic properties [4–7] . Among different nanomaterials, SNPs are ideal materials that have been widely used in biomedical applications [4,7–10] . Compared with traditional molecular-based therapeu tic drugs or contrast agents, biosynthesized SNPs, developed recently by our group, demonstrate multifunctional theranostic capabilities, such as: anticancer; antibacte rial; biocompatibility/drug delivery vehicle; and imaging facilitator for the treatment of cancer and other diseases  . The methanolic extract of Olax scandens leaf contains fluores cent phytochemicals/proteins that attach to biosynthesized SNPs, which exhibit strong fluorescence properties inside the cells. In addition, phytochemicals like octacosanol, β-sitosterol and glucosides of β-sitosterol, among others, conjugated with biosynthe sized SNPs exhibit antiproliferative activ ity. Again, release of silver ions from nano composites is another reason for anticancer activity of biosynthesized SNPs. Hence, the biosynthesized SNPs could be used as ther anostics tool for the treatment of cancer and other diseases  .
Chitta Ranjan Patra Author for correspondence: Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India Tel.: +91 40 2719 1480 [email protected]
Sudip Mukherjee Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India and Academy of Scientific and Innovative Research (AcSIR) Anusandhan Bhavan, 2 Rafi Marg, New Delhi 110 001, India
Rajesh Kotcherlakota Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
Medicinal use of SNPs SNPs have a long history of use as medici nal agents  . The 2009 article ‘History of the Medical Use of Silver’, demonstrated the potential application of silver compounds/
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Editorial Patra, Mukherjee & Kotcherlakota colloidal SNPs for various medical purposes from the beginning of ancient civilization  . Over time, inves tigators have shown the potential applications of SNPs for the treatment of various diseases including diabetes mellitus, wound healing, common colds, obesity, aller gies, psoriasis, microbial, fungal and viral infectious diseases, among others [9,10] . Other reports state that nanomedicine-based green synthesized SNPs show antibacterial effect against different bacteria [8,11] . According to published literature, SNPs could be used as a rapid and sensitive nanomedicine technique for detection of bacterial growth inhibition  . A recent report by Munger et al. demonstrates the undetect able toxicity of commercially available SNPs that were orally administered in healthy volunteers  . Most recently, our group has demonstrated the multifunc tional activities of biosynthesized SNPs that could be useful for future cancer theranostics  . Biosynthesized SNPs: multifunctional activities The synthesis of eco-friendly metal nanoparticles is a growing branch of nanoscience and nanotechnology for biomedical applications  . Generally, plants and plant-based phytochemicals, gum, algae, fungi, bac teria, viruses and several other living microorganisms have been used as reducing, stabilizing agents for the synthesis of nanoparticles. This approach has several advantages over conventional methods as an efficient, economically cheap and environmentally safe option  . However, there are a few drawbacks for the synthe sis of nanoparticles using green chemistry approach, such as: the green synthesis is a slow process; some times it is difficult to control the size of nanoparticles using biological sources; the exact mechanism for the synthesis of nanoparticles is poorly understood; and nonspecific conjugation of phytochemicals/fluorescent molecules/proteins during the synthesis of SNPs.
…we strongly believe that these silver nanoparticles will open a novel direction towards solving the various biomedical problems in the near future.
Our group has recently demonstrated an efficient green chemistry approach for the fabrication of colloi dal biosynthesized SNPs that is formed by the interac tion of silver nitrate (AgNO3) and Olax scandens leaf extract  . The leaf extract works as a reducing as well as stabilizing agent for nanoparticles. The well-char acterized nanoparticles show multifunctional activities (4–in-1 system): biocompatibility towards normal cells that makes it drug delivery vehicle; anticancer activ ity; antibacterial activity; and fluorescence properties. Beside our work, several investigators reported the anti
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cancer activity of biosynthesized SNPs towards in vitro and in vivo systems  . It is well established that green synthesized SNPs show nanomedicine-based antibacte rial effects against different bacteria [8,11] . Nanda et al. demonstrated the most sensitive antimicrobial activity against methicillin-resistant Staphylococcus aureus fol lowed by methicillin-resistant Staphylococcus epider midis and Streptococcus pyogenes  . Fayaz et al. showed the enhancement of antibacterial activities of ampicil lin, kanamycin, erythromycin and chloramphenicol in presence of biosynthesized SNPs compared with free antibiotics  . Recent reports suggest that biosynthe sized SNPs could be used for surface-enhanced Raman scattering based analytical applications along with antimicrobial activity  . Most recently, Homan et al. demonstrated the use of biosynthesized SNPs in bio medical imaging and sensing applications  . Most of the published literature has demonstrated either thera peutic (antibacterial/antiinflammatory, among others) or diagnostic (imaging/sensing) applications of SNPs in biology and medicine. To our knowledge, there were no reports demonstrating the multifunctional nature of biosynthesized SNPs, prior to our group’s recent publi cation. The versatile properties of biosynthesized SNPs (4-in-1 system) may offer unconventional novel ther anostic treatment strategies for cancer, bacterial and other diseases in the near future using a nanomedicine approach  . Taken together, we strongly believe that biosynthesized SNPs could be used as a nanomedicine for the next generation. However, the efficacy of these nanoparticles in mammals and its safety with in vivo use has not yet been well established. The following major issues and challenges should be addressed prop erly before translating this knowledge and technology into commercially available products for the treatment of cancer and other diseases. Toxicity, biosafety, biodegradability & clinical opportunity The potential adverse health effects, toxicity, bio safety of nanomaterials should be properly assessed in preclinical models before administration of these nanoparticles to the human body  . Historically, silver has been used as a therapeutic agent in medi cine  . According to literature, nanosilver has been used as a medicinal agent for more than 100 years  . Several groups have established the nontoxic nature of nano silver in in vitro conditions that are radically different from in vivo circumstances [15–17] . A recent study in zebrafish embryos suggests that the toxicity of silver nanoparticles is associated with bioavailable silver ions  . However, most recently, Munger et al. demonstrated undetectable toxicity after oral administration of commercially available silver
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Biosynthesized silver nanoparticles: a step forward for cancer theranostics?
nanoparticles in healthy volunteers  . This report sup ports further study of nano silver in clinical trials for the application of these nanoparticles in human being. Another critical issue is the biodegradability of SNPs. Zhou et al., demonstrated efficient renal clear ance of glutathione coated luminescent gold nanopar ticles  . This study suggests that biosynthesized SNPs coated with phytochemicals should be easily cleared from the body through urination during its therapeutic application in in vivo model. A recent report suggests that biogenic SNPs are usu ally less cyto-/geno-toxic in vivo compared with chem ically synthesized SNPs  . Green synthesized SNPs show strong antibacterial effect towards Gram-nega tive bacteria compared with Gram-positive bacteria in a dose dependent manner and it offers a clinical ultra sound gel with antibacterial property for inhibition of cross infections  . Future opportunities, challenges & directions The undetectable toxicity of SNPs in healthy volun teers demonstrated by Munger et al., suggests that bio synthesized SNPs could be used for cancer theranos tics in the near future  . The biocompatibility of our biosynthesized SNPs towards normal cells may provide a novel drug delivery vehicle for the treatment of can cer. The anticancer activity and fluorescence imaging property of our biosynthesized SNPs may provide a basis for the development of future cancer therapeu tics as well as diagnostics. Replacement of the conven References 1
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tional use of radiolabeled isotopes for the detection of tumors in the body (radiotherapy) by the fluoresence properties of biosynthesized SNPs may reduce side effects. In addition, SNPs show excellent antibacterial activities. Considering the all advantages of our SNPs, we strongly believe that these SNPs will open a novel direction towards solving the various biomedical prob lems in the near future. Moreover, intensive character ization and quality control of these SNPs are the essen tial steps to be taken into consideration before this technology can be available commercially. Considering all major challenges and issues, we hope biosynthesized SNPs might be successfully implemented as an afford able nanomedicine for the treatment of cancer, wound healing and other diseases in near future. Financial & competing interests disclosure This research was supported by the Ramanujan Fellowship grant (SR/S2/RJN-04/2010; GAP0305) from the Department of Science & Technology (DST), New Delhi and generous financial assistance from the Council of Scientific and Industrial Research (CSIR), New Delhi under the 12th Five-Year Plan project ‘Advanced Drug Delivery (ADD) systems’ (CSC0302). S Mukherjee is thankful to CSIR, New Delhi for the support of a Research Fellowship. The authors have 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. 8
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