An In vivo Study On Cobalt Ferrite Nanoparticles As Multi...
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TNT2018 Lecce (Italy) An In vivo Study On Cobalt Ferrite Nanoparticles As Multi-Modal Cancer Therapy Combining Intrinsic Toxicity and Hyperthermia Preethi Bala Balakrishnan 1,2 Federica Marinaro 3 , Niccolo Silvestri 1,2 , Tiziano Catelani 1 , Teresa Pellegrino 1 1 Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16162, Italy 2 University of Genova, DCCI, Via Dodecaneso 33, Genoa 16146, Italy 3 Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, United Kingdom [email protected] Magnetic nanoparticles under alternating magnetic field can convert the electromagnetic energy into thermal energy which, in turn can be exploited for hyperthermia (HT) therapy 1 . Besides Iron Oxide nanoparticles (IONPs) which are commonly used as heat hubs in magnetic hyperthermia, mixed ferrites of these IONPs with Manganese (Mn), Cobalt (Co) or Zinc (Zn) ions are also promising candidates for such magnetic HT treatment due to their improved magnetic properties. Cobalt ferrite nanocubes have shown very high specific adsorption rate (SAR) values (a measure of their heat performances) at clinically acceptable frequency and field conditions 2 . However, the use of Co-based nanoparticles for biomedical applications is still under debate. There are numerous evidences of intrinsic toxicity of CoFe 2 O 4 NPs in cellular studies, with a toxicity profile being highly dependent on the cell types and concentration tested 3 . Due to the proven cytotoxicity, not much exploration has been made on cobalt-based nanoparticles in in-vivo conditions. We synthesized 17nm cobalt ferrite nanocubes by thermal decomposition method, which showed improved SAR values at lower field and frequency conditions compared to standard IONPs of similar size and shape 2 . Here, on a xenograft murine mice model, we demonstrate the synergic effects of cobalt ferrite nanocubes as magnetic hyperthermia inducing agents and intrinsic toxic agent with controlled Co ion release. The intra-tumoral injection gave us the control, by specifically inducing toxicity only at to tumor mass, avoiding uncontrolled toxicity to other vital organs. The animals treated with the combination of cobalt- ferrite injection and magnetic hyperthermia showed complete reduction in tumor volume as compared to untreated control and other groups studied (without HT, IONPs with and without HT). Furthermore, the same group showed the longest survival of up to 200 days post treatment. The survived animals showed no signs of distress throughout the study. Histopathological, TEM and elemental analysis were performed on tumor and organs such as kidney, liver and spleen to study in detail the fate of these nanoparticles in vivo. With the results obtained in our study, we demonstrated that the intrinsic toxicity of the Co ions in the cobalt ferrite nanocubes, when exploited in a controlled environment, can replace the usage of other chemotherapeutic drugs and act as a self-standing multi-modal therapy, all working under lower dosage and acceptable hyperthermia limits. References [1] Klaus Maier-Hauff et al., Journal of Neuro- Oncology, 2007, 81 (1), pp 53–60. [2] Ayyappan Sathya et al., Chem. Mater., 2016, 28 (6), pp 1769–1780. [3] Limor Horev-Azaria et al., Particle and Fibre Toxicology 2013, 10:32. Figures Figure 1. Schematic representation of preparation of cobalt ferrite NPs for biomedical application (a) and their function as HT inducing agents (b). IR image of animal injected with Cobalt ferrite and subjected to HT(c). Image of animal before and after treatment.
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T N T 2 0 1 8 � L e c c e ( I t a l y )
An In vivo Study On Cobalt Ferrite Nanoparticles As Multi-Modal Cancer Therapy Combining Intrinsic Toxicity and Hyperthermia
PreethiBalaBalakrishnan1,2FedericaMarinaro3,NiccoloSilvestri1,2,TizianoCatelani1,TeresaPellegrino11IstitutoItalianodiTecnologia,ViaMorego30,Genoa16162,Italy2UniversityofGenova,DCCI,ViaDodecaneso33,Genoa16146,Italy3GurdonInstitute,UniversityofCambridge,CambridgeCB21QN,UnitedKingdom
Preethi.balakrishnan@iit.itMagneticnanoparticlesunderalternatingmagneticfield can convert the electromagnetic energy intothermalenergywhich, inturncanbeexploitedforhyperthermia (HT) therapy1. Besides Iron Oxidenanoparticles(IONPs)whicharecommonlyusedasheathubsinmagnetichyperthermia,mixedferritesof these IONPswithManganese (Mn), Cobalt (Co)or Zinc (Zn) ions are alsopromising candidates forsuchmagneticHTtreatmentduetotheirimprovedmagneticproperties.Cobaltferritenanocubeshaveshown very high specific adsorption rate (SAR)values (a measure of their heat performances) atclinicallyacceptable frequencyandfieldconditions2. However, the use of Co-based nanoparticles forbiomedicalapplications isstillunderdebate.Thereare numerous evidences of intrinsic toxicity ofCoFe2O4 NPs in cellular studies, with a toxicityprofile being highly dependent on the cell typesand concentration tested3. Due to the provencytotoxicity, notmuch exploration has beenmadeoncobalt-basednanoparticlesinin-vivoconditions.We synthesized 17nm cobalt ferrite nanocubes bythermal decomposition method, which showedimproved SAR values at lower field and frequencyconditions compared to standard IONPs of similarsizeandshape2.Here,onaxenograftmurinemicemodel, we demonstrate the synergic effects ofcobaltferritenanocubesasmagnetichyperthermiainducing agents and intrinsic toxic agent withcontrolled Co ion release. The intra-tumoralinjection gave us the control, by specificallyinducing toxicity only at to tumor mass, avoidinguncontrolled toxicity to other vital organs. Theanimals treated with the combination of cobalt-ferrite injection and magnetic hyperthermiashowed complete reduction in tumor volume ascompared to untreated control and other groupsstudied (without HT, IONPswith andwithout HT).Furthermore, the same group showed the longestsurvival of up to 200 days post treatment. The
survived animals showed no signs of distressthroughout the study. Histopathological, TEM andelemental analysis were performed on tumor andorganssuchaskidney, liverandspleentostudy indetail the fateof thesenanoparticles invivo.Withtheresultsobtainedinourstudy,wedemonstratedthattheintrinsictoxicityoftheCoionsinthecobaltferrite nanocubes, when exploited in a controlledenvironment, can replace the usage of otherchemotherapeuticdrugsandact as a self-standingmulti-modal therapy, all working under lowerdosageandacceptablehyperthermialimits.References[1] KlausMaier-Hauff et al., Journal of Neuro-
Oncology,2007,81(1),pp53–60.[2] Ayyappan Sathya et al., Chem. Mater., 2016,
28(6),pp1769–1780.[3] Limor Horev-Azaria et al., Particle and Fibre
Toxicology2013,10:32.Figures
Figure 1. Schematic representation of preparation ofcobalt ferrite NPs for biomedical application (a) andtheir function as HT inducing agents (b). IR image ofanimal injected with Cobalt ferrite and subjected toHT(c).Imageofanimalbeforeandaftertreatment.
