Facilitating Translational Nanomedicine via Predictive Safety Assessment
Authors: Vahid Mirshafiee, Wen Jiang, Bingbing Sun, Xiang Wang, Tian Xia
Journal: Molecular Therapy (2017)

Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nano-based therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications. As such, our aim in this mini-review is to discuss the current knowledge on predictive safety and structure-activity relationship (SAR) analysis of major ENMs at the developing stage, as well as the necessity of additional long-term toxicological analysis that would help to facilitate their transition into clinical practices. We focus on how the interaction of these nanomaterials with cells would trigger signaling pathways as molecular initiating events that lead to adverse outcomes. These mechanistic understandings would help to design safer ENMs with improved therapeutic efficacy in clinical settings. Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nano-based therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications. As such, our aim in this mini-review is to discuss the current knowledge on predictive safety and structure-activity relationship (SAR) analysis of major ENMs at the developing stage, as well as the necessity of additional long-term toxicological analysis that would help to facilitate their transition into clinical practices. We focus on how the interaction of these nanomaterials with cells would trigger signaling pathways as molecular initiating events that lead to adverse outcomes. These mechanistic understandings would help to design safer ENMs with improved therapeutic efficacy in clinical settings. During the past decades, engineered nanomaterials (ENMs) have been widely used in biomedical applications, such as nanomedicine, bioimaging, and tissue engineering, because of their unique biophysicochemical properties.1Yildirimer L. Thanh N.T.K. Loizidou M. Seifalian A.M. Toxicology and clinical potential of nanoparticles.Nano Today. 2011; 6: 585-607Crossref PubMed Scopus (496) Google Scholar, 2Zhang L. Gu F.X. Chan J.M. Wang A.Z. Langer R.S. Farokhzad O.C. Nanoparticles in medicine: therapeutic applications and developments.Clin. Pharmacol. Ther. 2008; 83: 761-769Crossref PubMed Scopus (1991) Google Scholar With regard to nanomedicine applications, ENMs could be formulated as drug carriers that deliver the therapeutic reagents within the human body and increase their bioavailability and blood circulation half-life.2Zhang L. Gu F.X. Chan J.M. Wang A.Z. Langer R.S. Farokhzad O.C. Nanoparticles in medicine: therapeutic applications and developments.Clin. Pharmacol. Ther. 2008; 83: 761-769Crossref PubMed Scopus (1991) Google Scholar Moreover, these nanocarriers could be functionalized to deliver the drug specifically to the desired target tissues (e.g., tumors) and release the payload sustainably over long periods, thereby eliminating the necessity of multiple drug administration and reducing its cytotoxic side effects toward healthy cells.2Zhang L. Gu F.X. Chan J.M. Wang A.Z. Langer R.S. Farokhzad O.C. Nanoparticles in medicine: therapeutic applications and developments.Clin. Pharmacol. Ther. 2008; 83: 761-769Crossref PubMed Scopus (1991) Google Scholar In addition to their implementation in drug delivery, ENMs could be used for diagnostic and imaging purposes that would help to monitor the disease and administer the treatment more accurately.2Zhang L. Gu F.X. Chan J.M. Wang A.Z. Langer R.S. Farokhzad O.C. Nanoparticles in medicine: therapeutic applications and developments.Clin. Pharmacol. Ther. 2008; 83: 761-769Crossref PubMed Scopus (1991) Google Scholar Past research in nanomedicine has led to the design of various nanomaterial-based therapeutic and diagnostic systems that are being investigated in experimental stages (e.g., in vitro and in vivo) and clinical trials or are commercially available to the corresponding patients (Table 1). Most commercialized nanomaterial-based therapeutic reagents use lipids, proteins, and polymers that could self-assemble and biodegrade with few side effects.3Bozzuto G. Molinari A. Liposomes as nanomedical devices.Int. J. Nanomedicine. 2015; 10: 975-999Crossref PubMed Scopus (1285) Google Scholar Because of high biocompatibility of lipids, several commercial liposome-drug formulations have been developed, mostly relying on polyethylene glycol (PEG)-conjugated lipids, such as DOXIL, AmBisome, Epaxal, and Inflexal V, and are under clinical trials focusing on various types of disease treatments.4Sercombe L. Veerati T. Moheimani F. Wu S.Y. Sood A.K. Hua S. Advances and challenges of liposome assisted drug delivery.Front. Pharmacol. 2015; 6: 286Crossref PubMed Scopus (1301) Google Scholar, 5Chang H.I. Yeh M.K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy.Int. J. Nanomedicine. 2012; 7: 49-60PubMed Google Scholar Polymer-based nanoparticles (NPs) also present low toxicity, but their surface functionalization may affect their safety. The most commonly used materials include PEG, ploy(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL).6Li C. Wallace S. Polymer-drug conjugates: recent development in clinical oncology.Adv. Drug Deliv. Rev. 2008; 60: 886-898Crossref PubMed Scopus (377) Google Scholar, 7Prabhu R.H. Patravale V.B. Joshi M.D. Polymeric nanoparticles for targeted treatment in oncology: current insights.Int. J. Nanomedicine. 2015; 10: 1001-1018PubMed Google Scholar Some polymer-based therapeutics, such as Zinostatin Stimalmer, Oncaspar PEG-L-asparaginase, and Neulasta PEG-GCSF, have been clinically approved for cancer treatment, while more formulations are undergoing clinical investigations.7Prabhu R.H. Patravale V.B. Joshi M.D. Polymeric nanoparticles for targeted treatment in oncology: current insights.Int. J. Nanomedicine. 2015; 10: 1001-1018PubMed Google Scholar Although these clinically approved nano-based treatments exhibit promising results with reduced hazard potential, they have some drawbacks. For example, liposome-based therapeutic NPs lack sufficient mechanical stability, and their undesirable disruption within the in vivo environment could lead to the burst release of their therapeutic cargo.8Liu X. Situ A. Kang Y. Villabroza K.R. Liao Y. Chang C.H. Donahue T. Nel A.E. Meng H. Irinotecan delivery by lipid-coated mesoporous silica nanoparticles shows improved efficacy and safety over liposomes for pancreatic cancer.ACS Nano. 2016; 10: 2702-2715Crossref PubMed Scopus (175) Google Scholar In addition, liposome- and polymer-based nanotherapeutics that use PEG-lipid conjugates in their structure could induce complement activation-related pseudo-allergic reactions.9Crist R.M. Grossman J.H. Patri A.K. Stern S.T. Dobrovolskaia M.A. Adiseshaiah P.P. Clogston J.D. McNeil S.E. Common pitfalls in nanotechnology: lessons learned from NCI's Nanotechnology Characterization Laboratory.Integr. Biol. 2013; 5: 66-73Crossref Google Scholar, 10Moghimi S.M. Andersen A.J. Hashemi S.H. Lettiero B. Ahmadvand D. Hunter A.C. Andresen T.L. Hamad I. Szebeni J. Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead.J. Control. Release. 2010; 146: 175-181Crossref PubMed Scopus (161) Google Scholar Thus, the necessity to address the challenges associated with these nanomaterial-based drug delivery and diagnostic systems has promoted the development of newly designed ENMs with unique characteristics that could enhance the efficacy and accuracy of medical treatments. For example, multifunctional nanocarriers with cationic surface functionalization are developed for in vitro and in vivo delivery of nucleic acids, including DNA and RNA.11Meng H. Liong M. Xia T. Li Z. Ji Z. Zink J.I. Nel A.E. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line.ACS Nano. 2010; 4: 4539-4550Crossref PubMed Scopus (763) Google Scholar, 12Xia T. Kovochich M. Liong M. Meng H. Kabehie S. George S. Zink J.I. Nel A.E. Polyethyleneimine coating enhances the cellular uptake of mesoporous silica nanoparticles and allows safe delivery of siRNA and DNA constructs.ACS Nano. 2009; 3: 3273-3286Crossref PubMed Scopus (754) Google Scholar In addition, a new class of luminescent nanoprobes termed as upconversion nanoparticles (UCNPs) has been developed that presents higher photostability compared to traditional fluorophores and has growing applications in bioimaging and photodynamic therapy. However, it is important to thoroughly investigate the interaction of these ENMs with biological systems and assess their toxicity before making judgements on their translational value in nanomedicine. Even though there are many types of nanomaterials with novel designs, such as biomimetic NPs and nanolipoproteins that were shown to be applicable for therapeutic purposes,13Fischer N.O. Weilhammer D.R. Dunkle A. Thomas C. Hwang M. Corzett M. Lychak C. Mayer W. Urbin S. Collette N. et al.Evaluation of nanolipoprotein particles (NLPs) as an in vivo delivery platform.PLoS ONE. 2014; 9: e93342Crossref PubMed Scopus (40) Google Scholar this mini-review specifically focuses on some of the most common inorganic ENMs, including colloidal solid silica NPs (Si-NPs), rare-earth based nanomaterials, gold NPs (Au-NPs) and silver NPs (Ag-NPs), superparamagnetic iron oxide nanoparticles (SPIONs), and quantum dots (QDs), as well as carbonaceous nanomaterials that are being assessed in numerous preclinical studies. We aim to present how recent mechanistic studies based on structure-activity relationship (SAR) analysis could help to design safer ENMs for therapeutic and diagnostic applications.Table 1Biomedical Applications, Development Stages, and Biological Effects of ENM LibrariesNPsMaterialsApplicationsDevelopment StagesToxicityReferencesPolymer-based NPspolymer NPs, micelles, dendrimers made by PEG, PLGA, PLA, PCL, or polypeptidescancer therapygene deliverydrug deliverybiomedical diagnosisbioimagingcommercialized, clinical trialslow with possible toxicity induced by linkers for surface functionalization7Prabhu R.H. Patravale V.B. Joshi M.D. Polymeric nanoparticles for targeted treatment in oncology: current insights.Int. J. Nanomedicine. 2015; 10: 1001-1018PubMed Google Scholar, 9Crist R.M. Grossman J.H. Patri A.K. Stern S.T. Dobrovolskaia M.A. Adiseshaiah P.P. Clogston J.D. McNeil S.E. Common pitfalls in nanotechnology: lessons learned from NCI's Nanotechnology Characterization Laboratory.Integr. Biol. 2013; 5: 66-73Crossref Google ScholarLiposomeslipids, cross-linked lipids, PEG-lipid conjugatescancer therapygene deliverydrug deliverybiomedical diagnosiscommercialized, clinical trialslow but with potential toxicity induced by surface modification and degradation4Sercombe L. Veerati T. Moheimani F. Wu S.Y. Sood A.K. Hua S. Advances and challenges of liposome assisted drug delivery.Front. Pharmacol. 2015; 6: 286Crossref PubMed Scopus (1301) Google Scholar, 5Chang H.I. Yeh M.K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy.Int. J. Nanomedicine. 2012; 7: 49-60PubMed Google Scholar, 8Liu X. Situ A. Kang Y. Villabroza K.R. Liao Y. Chang C.H. Donahue T. Nel A.E. Meng H. 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Synthetic Si-NPs exist in different forms, including crystalline (e.g., quartz) and amorphous (e.g., fumed, mesoporous, and colloidal) particles, depending on their synthesis process, thus displaying different physicochemical properties (e.g., crystallinity, porosity, and surface reactivity).16Napierska D. Thomassen L.C.J. Lison D. Martens J.A. Hoet P.H. The nanosilica hazard: another variable entity.Part. Fibre Toxicol. 2010; 7: 39Crossref PubMed Scopus (591) Google Scholar, 17Sun B. Pokhrel S. Dunphy D.R. Zhang H. Ji Z. Wang X. Wang M. Liao Y.P. Chang C.H. Dong J. et al.Reduction of acute inflammatory effects of fumed silica nanoparticles in the lung by adjusting silanol display through calcination and metal doping.ACS Nano. 2015; 9: 9357-9372Crossref PubMed Scopus (90) Google Scholar Within the recent decades, colloidal solid Si-NPs have been applied in numerous therapeutic and diagnostic applications,18Tang L. Cheng J. 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Biological applications of rare-earth based nanoparticles.ACS Nano. 2011; 5: 8488-8505Crossref PubMed Scopus (495) Google Scholar In addition to imaging applications, UCNPs could be applied for photodynamic therapy and cancer treatment.32Ai X. Ho C.J.H. Aw J. Attia A.B.E. Mu J. Wang Y. Wang X. Wang Y. Liu X. Chen H. et al.In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics.Nat. Commun. 2016; 7: 10432Crossref PubMed Scopus (328) Google Scholar However, the growing application of RE-based nanomaterials could increase the possibility of human exposure and adverse health outcomes. For instance, an increasing number of studies reported a direct correlation between administration of gadolinium (Gd)-based contrast agents and induction of nephrogenic systemic fibrosis (NSF) in patients with renal deficiency.33Marckmann P. Skov L. Rossen K. Dupont A. Damholt M.B. Heaf J.G. Thomsen H.S. 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The study demonstrated that enhanced dissolution of these NPs and shedding of REO ions within the acidic environment of the lysosome leads to the deposition of REPO4 complexes on the NP's surface and particle transformation into urchin-shaped structures. Following the depletion of free phosphate groups within the lysosome, the REO ions could strip the phosphates from the lysosome's lipid membrane and induce lysosomal damage. This phenomenon is followed by the release of lysosomal contents including cathepsin B, leading to activation of nonobese diabetic (NOD)-like receptor protein 3 (NLRP3) inflammasome and release of interleukin-1β (IL-1β), which eventually triggers a series o