Editorial
Nanomedicine and neurodegenerative disorders: so close yet so far 1.
Introduction
2.
Nanomedicine and brain delivery of drugs
3.
Critical aspects, distances to be shorten, translatability of
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
nanomedicine to clinic
Giovanni Tosi†, Maria Angela Vandelli, Flavio Forni & Barbara Ruozi University of Modena and Reggio Emilia, Department of Life Sciences, Nanomedicine Group, Modena, Italy
This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases. Keywords: brain, drug delivery and targeting, nanomedicine, neurodegenerative disorders Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Neurodegenerative disorders, as Alzheimer ’s disease (AD) and Parkinson’s disease (PD), are amongst the top causes for morbidity and mortality in adults besides heart disease, cancer and stroke. As an example, AD represents the most prevalent type (60%) of dementia, > 30 million people suffering from AD worldwide and with provision of increase in AD progression and distribution. The social, economic and health impact of AD is therefore more than significant. The unsolved mystery of mechanisms of such neurodegenerative disorders and lack of effective clinical therapeutics make them ‘pandemic’ diseases [1]. Possible reasons for the failure in treatment and management of neurodegenerative disorders are: i) drugs currently used are only symptomatic, not preventing the progressive pathology, but only helping to ameliorate the symptoms; ii) yet unvalidated early diagnostic markers with only ‘probable’ or ‘possible’ diagnosis; iii) presence of blood--brain barrier (BBB), defensive barrier of CNS, hampering the passage of drugs to the ‘site of action’. Innovative nanomedicines, that is, drug delivery systems as polymeric nanoparticles (NPs), liposomes (LPs) and others nanodrugs, engineered on their surface to cross the BBB and featured by a decreased invasiveness and the ability in exploiting a CNS drug delivery, were proposed and investigated as strategic approach in diagnoses, prevention and treatment of neurodegenerative diseases, as AD and PD [2,3]. Moreover, the lack of clear pathogenetic cascade for brain disorders and the absence of effective clinical therapeutics link brain disorders creating a common collective problem. 2.
Nanomedicine and brain delivery of drugs
“A nanomedicine for every CNS disorders does not exist”. This sentence seems to be obvious, but, unfortunately, it is the main driver for most of the researches in the field. In fact, the point is that, at the very initial era of nanomedicine research, 20 years ago, the scientists, although understanding the potential of nanomedicine for CNS disorders, were wrongly persuaded that this approach would represent a sort of ‘nanoPanacea’. 10.1517/17425247.2015.1041374 © 2015 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
G. Tosi et al.
In the light of the experiences of many researches, the reality is that many factors should be reconsidered and quickly become blocks for development of nanomedicine for neurodisorders. This means that the design of a nanomedicine for neurodegenerative disorders must take into account inputs deriving from nanotechnology, pathology, neurobiology and pharmaceutical industry. As exposed before, polymeric NPs or lipophilic LPs could provide for the protection of the embedded drug and strongly give the chance to develop and optimize therapy since engineered drug delivery systems are specifically designed to be ‘ultra-selective’ and therefore able to target specific diseased cell population. In order to obtain ‘smart’ drug delivery systems, engineering of the surface of the nanocarriers with selective ligands was mostly investigated in the case of CNS drug targeting and delivery. Thanks to surface engineering based on covalent bonds with appropriate ligands, these smart ‘taxies’ could promote direct interaction with transport systems [4,5], triggering their BBB crossing. These ligands could be natural substrates or targeting moieties (such as transferrin (TfR), insulin (InsR) and thiamine, but also synthetic or natural peptides) and antibodies. Generally, all these strategies exploit transport pathways (endocytosis, transcytosis) after interaction with receptors present at BBB endothelial cell level, such as TfR, InsR or Leptin. The use of natural endogenous ligands was progressively substituted by the use of specific antibodies (mAb) or receptor-agonist or endogenous-like molecules, linked onto NPs surfaces to get BBB crossing and to avoid possible competitive events [6-8]. As some kinds of receptors, present at BBB capillary endothelium, can mediate transcytosis of circulating peptides across the BBB, peptide-based approaches (‘chimeric peptide technology’) were also investigated as alternative strategies. This very elegant innovation was focusing on neurodiagnostic and neurotherapeutics aims, because the conjugation of brain targeting vector with a drug unable to cross the BBB could lead to an efficacious BBB translocation [9]. As another example, a new strategy for brain targeting based on NPs by using poly-lactide-co-glycolide conjugated with peptides [10,11] was recently demonstrated to be efficacious after systemic administration in different animal models. Nanomedicine-related papers globally indicate that the advantages of this nanostrategy for treatment of CNS pathology mainly consist of the feasibility of nanocarriers and the possibility of engineering the surface of these systems with selective and tailored targetor ligands. This last advantage especially allows a specific and selective drug delivery and targeting. This encouraging evidences lead to consider nanomedicine to be very close to clinic application, but it is, unfortunately, far away. Many critical aspects, on nanotechnology area (regarding formualtive parameters, surface chemistry and characterization) and on neuropathology areas (BBB state, altered cellular metabolism, cell-to-cell dynamics), remain to be solved. In 2
the following section, some important aspects, possible causes of the slowing of clinical application of nanomedicine, are reported: not only criticisms but also a sort of ‘contingency plan’ against this scientific immobility.
Critical aspects, distances to be shorten, translatability of nanomedicine to clinic
3.
Aiming to improve the chances of translatability of nanomedicines to clinic, two important goals should be addressed; the toxicity/safety profiles of these ‘novel nanodrugs’ and the identification of scale-up processes needed in industrial production [12-15]. Thus, to implement nanomedicines for neurodegenerative disorders, the creation of focused tailored network in which specialized physicians, neurobiologists, nanotechnologists, pharmacologists and toxicologists, sharing all skills and competences, is highly required. The combined efforts of such specialized teams will create the needed background and interdisciplinary knowledge which could finally help the development and application of nanomedicine to CNS disorder. In particular, the scientific community witnessed the defragmentation of the knowledge into scientific, clinical and industrial fields; the main effort will be to consider these isolated aspects as actors to establish architecture of competences varying from basic knowledge of the pathology and of the BBB, up to nanomedicine-based interventions with focus on both in vivo models and toxicological aspects. As for example, the following main themes should be investigated by establishing high level of collaboration and networking. Theme 1. Neurobiology of disease and nanomedicine: A broad knowledge on different aspects of neuropathologies should be implemented, with particular focus on the role and possible interaction with nanomedicine. As examples, anatomy and pathology of neurodegenerative disease, the role of the BBB in healthy and diseased brains, individuation of targets for neurodegenerative disorders should be clearly assessed. In this view, the identification of mechanism of neurodegeneration and causes of neurological disorders, a major focus on the role of neuroinflammation in CNS diseases along with a general better and tailored knowledge on the molecular neurobiology of the diseases could help in the rationale design of efficacious nanomedicines. Theme 2. Neurotherapeutics of nanomedicine: In this field, the refinement of strategies for CNS targeting, the development of novel Drug Delivery Systems for therapy and imaging of CNS diseases, along with the identification of possible approaches for exploitation of BBB crossing pathways
Expert Opin. Drug Deliv. (2015) 12(7)
Nanomedicine and neurodegenerative disorders: so close yet so far
Neurobiology of disease and nanomedicine
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
Nanomedicine scale up
Neurotherapeutics of nanomedicine
Neurotoxicology of nanomedicine
Translatability of nanoneurotherapeutics
Figure 1. Flow of issues for nanomedicine development.
(in healthy and diseased brains) should be reached as final goals. The introduction of suitable ligands for CNS targeting will be designed on the basis of a rationale planning deriving from neurobiology inputs, as well as directed to a real applicability to humans. This will mean to avoid the study of ligands which will be surely ineffective in humans (for endogenous competition, as example), trying to set up technologies able to trigger BBB crossing and CNS targeting in a very specific manner. Theme 3. Translatability of nano-neurotherapeutics: One of the most risky and tricky aspects is related to the bench-to-bedside process; in this view, above a clear horizontal assessment of the main advantages of nanomedicines compared to state-of-the-art of therapeutic options in clinics, a strong stimulus should be given also by industrial and medical feedback on the use and application of nanomedicine. Moreover, the evaluation of the benefits and reliability of animal models for neurodegenerative diseases should be discussed in depth. Theme 4. Neurotoxicology of nanomedicine: Safety of nanomedicine is a priority to reach clinical applicability, relevant and strictly connected to the previous one. Bio-safety and biointeraction of nanomedicine are pivotal steps to better clarify their role in the clinic. Thus, proper checks in animal models (BBB state, neurodegenerated brains key factors), along with univocal protocols for nanotoxicology, should be performed and developed at the same time of efficacy studies. Reliable test methods are needed to predict human nanotoxicity according to REACH (EC 1907/2006)
and to meet the ‘3Rs principle’ for animal experiments. In summary, univocal protocols for nanotoxicology is an urgent need. Theme 5. Nanomedicine scale up: This theme is of extreme importance as the identification of industrial processes for scale up of nanocarriers is a pivotal requirement. Along with money effort and cost-benefit ration, the safety and toxicity in nanocarrier production, a deep consideration of the feasibility of laboratory protocols in nanocarriers formulation will help both academia and industry to follow the same pave (Figure 1). By reaching these goals, benefits will be assessed at different levels, that is, society, health, science and technology. These novel strategies for neurodegenerative disorders will therefore produce dramatic impacts: i) on health-care and society especially since neurodegenerative disorders pose urgent need for such strategies; ii) on innovation in science, as nanomedicine would lead to new approaches for site-directed drug delivery or to image the development of the pathology with interesting evolution into nanotheranostic entities; iii) on technology as nanotechnology is now at the cutting edge innovation, as proven by the number of patents, papers and on-going clinical trials. In conclusion, as a wish and inspiring feeling, the future directions will drive all scientists toward the creation of mutual relationships on this know-how to finally get to neuro-nanomedicine.
Expert Opin. Drug Deliv. (2015) 12(7)
3
G. Tosi et al.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
6.
Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Rel 2013;172:962--74
1.
7.
Gabathuler R. Development of new peptide vectors for the transport of therapeutic across the blood-brain barrier. Ther Deliv 2010;1:571--86
2.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
3.
..
4.
..
5.
..
4
Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011;7:137--52 Andrieux K, Couvreur P. Nanomedicine as a promising approach for the treatment and diagnosis of brain diseases: the example of Alzheimer’s disease. Ann Pharm Fr 2013;71:225--33 Ruozi B, Belletti D, Pederzoli F, et al. Nanotechnology and Alzheimer’s disease: what has been done and what to do. Curr Med Chem 2014;21:4169--85 Good review on the possibility of nanomedicine in therapy and diagnosis Alzheimer’s disease. Agrawal U, Chashoo G, Sharma PR, et al. Tailored polymer-lipid hybrid nanoparticles for the delivery of drug conjugate: Dual strategy for brain targeting. Colloids Surf B Biointerfaces 2015;126:414--25 Very elegant and innovative strategies for brain delivery by double-ligands surface engineering of nanoparticles. Newton HB. Advances in strategies to improve drug delivery to brain tumors. Expert Rev Neurother 2006;6:1495--509 Interesting review on the application and feasibility of nanomedicine in tumors of the CNS.
8.
..
9.
10.
11.
.
Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. Neurobiol Dis 2010;37:48--57 Review on the advantages and disadvantages of the strategies for BBB crossing and CNS therapy. Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 2014;81:49--60 Tosi G, Bortot B, Ruozi B, et al. Potential use of polymeric nanoparticles for drug delivery across the blood-brain barrier. Curr Med Chem 2013;20:2212--25 Vilella A, Tosi G, Grabrucker AM, et al. Insight on the fate of CNS-targeted nanoparticles. Part I: Rab5-dependent cell-specific uptake and distribution. J Control Rel 2014;174:195--201 Good paper on the fate of nanomedicine inside the CNS.
Expert Opin. Drug Deliv. (2015) 12(7)
12.
Teli MK, Mutalik S, Rajanikant GK. Nanotechnology and nanomedicine: going small means aiming big. Curr Pharm Des 2010;16:1882--92
13.
Pautler M, Brenner S. Nanomedicine: promises and challenges for the future of public health. Int J Nanomedicine 2010;5:803--9
14.
Murday JS, Siegel RW, Stein J, et al. Translational nanomedicine: status assessment and opportunities. Nanomedicine 2009;5:251--73 Very good review on the analysis of the transalatability of nanomedicine with clear assessment of limits and advantages.
..
15.
Wagner V, Dullaart A, Bock AK, et al. The emerging nanomedicine landscape. Nature Biotech 2006;24:1211--17
Affiliation
Giovanni Tosi†, Maria Angela Vandelli, Flavio Forni & Barbara Ruozi † Author for correspondence Professor, University of Modena and Reggio Emilia, Department of Life Sciences, Nanomedicine Group, 41124, Modena, Italy Tel: +39 059 2055128; Fax: +39 059 2055131; E-mail: [email protected]
Nanomedicine and neurodegenerative disorders: so close yet so far 1.
Introduction
2.
Nanomedicine and brain delivery of drugs
3.
Critical aspects, distances to be shorten, translatability of
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
nanomedicine to clinic
Giovanni Tosi†, Maria Angela Vandelli, Flavio Forni & Barbara Ruozi University of Modena and Reggio Emilia, Department of Life Sciences, Nanomedicine Group, Modena, Italy
This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases. Keywords: brain, drug delivery and targeting, nanomedicine, neurodegenerative disorders Expert Opin. Drug Deliv. [Early Online]
1.
Introduction
Neurodegenerative disorders, as Alzheimer ’s disease (AD) and Parkinson’s disease (PD), are amongst the top causes for morbidity and mortality in adults besides heart disease, cancer and stroke. As an example, AD represents the most prevalent type (60%) of dementia, > 30 million people suffering from AD worldwide and with provision of increase in AD progression and distribution. The social, economic and health impact of AD is therefore more than significant. The unsolved mystery of mechanisms of such neurodegenerative disorders and lack of effective clinical therapeutics make them ‘pandemic’ diseases [1]. Possible reasons for the failure in treatment and management of neurodegenerative disorders are: i) drugs currently used are only symptomatic, not preventing the progressive pathology, but only helping to ameliorate the symptoms; ii) yet unvalidated early diagnostic markers with only ‘probable’ or ‘possible’ diagnosis; iii) presence of blood--brain barrier (BBB), defensive barrier of CNS, hampering the passage of drugs to the ‘site of action’. Innovative nanomedicines, that is, drug delivery systems as polymeric nanoparticles (NPs), liposomes (LPs) and others nanodrugs, engineered on their surface to cross the BBB and featured by a decreased invasiveness and the ability in exploiting a CNS drug delivery, were proposed and investigated as strategic approach in diagnoses, prevention and treatment of neurodegenerative diseases, as AD and PD [2,3]. Moreover, the lack of clear pathogenetic cascade for brain disorders and the absence of effective clinical therapeutics link brain disorders creating a common collective problem. 2.
Nanomedicine and brain delivery of drugs
“A nanomedicine for every CNS disorders does not exist”. This sentence seems to be obvious, but, unfortunately, it is the main driver for most of the researches in the field. In fact, the point is that, at the very initial era of nanomedicine research, 20 years ago, the scientists, although understanding the potential of nanomedicine for CNS disorders, were wrongly persuaded that this approach would represent a sort of ‘nanoPanacea’. 10.1517/17425247.2015.1041374 © 2015 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
G. Tosi et al.
In the light of the experiences of many researches, the reality is that many factors should be reconsidered and quickly become blocks for development of nanomedicine for neurodisorders. This means that the design of a nanomedicine for neurodegenerative disorders must take into account inputs deriving from nanotechnology, pathology, neurobiology and pharmaceutical industry. As exposed before, polymeric NPs or lipophilic LPs could provide for the protection of the embedded drug and strongly give the chance to develop and optimize therapy since engineered drug delivery systems are specifically designed to be ‘ultra-selective’ and therefore able to target specific diseased cell population. In order to obtain ‘smart’ drug delivery systems, engineering of the surface of the nanocarriers with selective ligands was mostly investigated in the case of CNS drug targeting and delivery. Thanks to surface engineering based on covalent bonds with appropriate ligands, these smart ‘taxies’ could promote direct interaction with transport systems [4,5], triggering their BBB crossing. These ligands could be natural substrates or targeting moieties (such as transferrin (TfR), insulin (InsR) and thiamine, but also synthetic or natural peptides) and antibodies. Generally, all these strategies exploit transport pathways (endocytosis, transcytosis) after interaction with receptors present at BBB endothelial cell level, such as TfR, InsR or Leptin. The use of natural endogenous ligands was progressively substituted by the use of specific antibodies (mAb) or receptor-agonist or endogenous-like molecules, linked onto NPs surfaces to get BBB crossing and to avoid possible competitive events [6-8]. As some kinds of receptors, present at BBB capillary endothelium, can mediate transcytosis of circulating peptides across the BBB, peptide-based approaches (‘chimeric peptide technology’) were also investigated as alternative strategies. This very elegant innovation was focusing on neurodiagnostic and neurotherapeutics aims, because the conjugation of brain targeting vector with a drug unable to cross the BBB could lead to an efficacious BBB translocation [9]. As another example, a new strategy for brain targeting based on NPs by using poly-lactide-co-glycolide conjugated with peptides [10,11] was recently demonstrated to be efficacious after systemic administration in different animal models. Nanomedicine-related papers globally indicate that the advantages of this nanostrategy for treatment of CNS pathology mainly consist of the feasibility of nanocarriers and the possibility of engineering the surface of these systems with selective and tailored targetor ligands. This last advantage especially allows a specific and selective drug delivery and targeting. This encouraging evidences lead to consider nanomedicine to be very close to clinic application, but it is, unfortunately, far away. Many critical aspects, on nanotechnology area (regarding formualtive parameters, surface chemistry and characterization) and on neuropathology areas (BBB state, altered cellular metabolism, cell-to-cell dynamics), remain to be solved. In 2
the following section, some important aspects, possible causes of the slowing of clinical application of nanomedicine, are reported: not only criticisms but also a sort of ‘contingency plan’ against this scientific immobility.
Critical aspects, distances to be shorten, translatability of nanomedicine to clinic
3.
Aiming to improve the chances of translatability of nanomedicines to clinic, two important goals should be addressed; the toxicity/safety profiles of these ‘novel nanodrugs’ and the identification of scale-up processes needed in industrial production [12-15]. Thus, to implement nanomedicines for neurodegenerative disorders, the creation of focused tailored network in which specialized physicians, neurobiologists, nanotechnologists, pharmacologists and toxicologists, sharing all skills and competences, is highly required. The combined efforts of such specialized teams will create the needed background and interdisciplinary knowledge which could finally help the development and application of nanomedicine to CNS disorder. In particular, the scientific community witnessed the defragmentation of the knowledge into scientific, clinical and industrial fields; the main effort will be to consider these isolated aspects as actors to establish architecture of competences varying from basic knowledge of the pathology and of the BBB, up to nanomedicine-based interventions with focus on both in vivo models and toxicological aspects. As for example, the following main themes should be investigated by establishing high level of collaboration and networking. Theme 1. Neurobiology of disease and nanomedicine: A broad knowledge on different aspects of neuropathologies should be implemented, with particular focus on the role and possible interaction with nanomedicine. As examples, anatomy and pathology of neurodegenerative disease, the role of the BBB in healthy and diseased brains, individuation of targets for neurodegenerative disorders should be clearly assessed. In this view, the identification of mechanism of neurodegeneration and causes of neurological disorders, a major focus on the role of neuroinflammation in CNS diseases along with a general better and tailored knowledge on the molecular neurobiology of the diseases could help in the rationale design of efficacious nanomedicines. Theme 2. Neurotherapeutics of nanomedicine: In this field, the refinement of strategies for CNS targeting, the development of novel Drug Delivery Systems for therapy and imaging of CNS diseases, along with the identification of possible approaches for exploitation of BBB crossing pathways
Expert Opin. Drug Deliv. (2015) 12(7)
Nanomedicine and neurodegenerative disorders: so close yet so far
Neurobiology of disease and nanomedicine
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
Nanomedicine scale up
Neurotherapeutics of nanomedicine
Neurotoxicology of nanomedicine
Translatability of nanoneurotherapeutics
Figure 1. Flow of issues for nanomedicine development.
(in healthy and diseased brains) should be reached as final goals. The introduction of suitable ligands for CNS targeting will be designed on the basis of a rationale planning deriving from neurobiology inputs, as well as directed to a real applicability to humans. This will mean to avoid the study of ligands which will be surely ineffective in humans (for endogenous competition, as example), trying to set up technologies able to trigger BBB crossing and CNS targeting in a very specific manner. Theme 3. Translatability of nano-neurotherapeutics: One of the most risky and tricky aspects is related to the bench-to-bedside process; in this view, above a clear horizontal assessment of the main advantages of nanomedicines compared to state-of-the-art of therapeutic options in clinics, a strong stimulus should be given also by industrial and medical feedback on the use and application of nanomedicine. Moreover, the evaluation of the benefits and reliability of animal models for neurodegenerative diseases should be discussed in depth. Theme 4. Neurotoxicology of nanomedicine: Safety of nanomedicine is a priority to reach clinical applicability, relevant and strictly connected to the previous one. Bio-safety and biointeraction of nanomedicine are pivotal steps to better clarify their role in the clinic. Thus, proper checks in animal models (BBB state, neurodegenerated brains key factors), along with univocal protocols for nanotoxicology, should be performed and developed at the same time of efficacy studies. Reliable test methods are needed to predict human nanotoxicity according to REACH (EC 1907/2006)
and to meet the ‘3Rs principle’ for animal experiments. In summary, univocal protocols for nanotoxicology is an urgent need. Theme 5. Nanomedicine scale up: This theme is of extreme importance as the identification of industrial processes for scale up of nanocarriers is a pivotal requirement. Along with money effort and cost-benefit ration, the safety and toxicity in nanocarrier production, a deep consideration of the feasibility of laboratory protocols in nanocarriers formulation will help both academia and industry to follow the same pave (Figure 1). By reaching these goals, benefits will be assessed at different levels, that is, society, health, science and technology. These novel strategies for neurodegenerative disorders will therefore produce dramatic impacts: i) on health-care and society especially since neurodegenerative disorders pose urgent need for such strategies; ii) on innovation in science, as nanomedicine would lead to new approaches for site-directed drug delivery or to image the development of the pathology with interesting evolution into nanotheranostic entities; iii) on technology as nanotechnology is now at the cutting edge innovation, as proven by the number of patents, papers and on-going clinical trials. In conclusion, as a wish and inspiring feeling, the future directions will drive all scientists toward the creation of mutual relationships on this know-how to finally get to neuro-nanomedicine.
Expert Opin. Drug Deliv. (2015) 12(7)
3
G. Tosi et al.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
6.
Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Rel 2013;172:962--74
1.
7.
Gabathuler R. Development of new peptide vectors for the transport of therapeutic across the blood-brain barrier. Ther Deliv 2010;1:571--86
2.
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Gazi Univ. on 05/05/15 For personal use only.
in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
3.
..
4.
..
5.
..
4
Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011;7:137--52 Andrieux K, Couvreur P. Nanomedicine as a promising approach for the treatment and diagnosis of brain diseases: the example of Alzheimer’s disease. Ann Pharm Fr 2013;71:225--33 Ruozi B, Belletti D, Pederzoli F, et al. Nanotechnology and Alzheimer’s disease: what has been done and what to do. Curr Med Chem 2014;21:4169--85 Good review on the possibility of nanomedicine in therapy and diagnosis Alzheimer’s disease. Agrawal U, Chashoo G, Sharma PR, et al. Tailored polymer-lipid hybrid nanoparticles for the delivery of drug conjugate: Dual strategy for brain targeting. Colloids Surf B Biointerfaces 2015;126:414--25 Very elegant and innovative strategies for brain delivery by double-ligands surface engineering of nanoparticles. Newton HB. Advances in strategies to improve drug delivery to brain tumors. Expert Rev Neurother 2006;6:1495--509 Interesting review on the application and feasibility of nanomedicine in tumors of the CNS.
8.
..
9.
10.
11.
.
Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. Neurobiol Dis 2010;37:48--57 Review on the advantages and disadvantages of the strategies for BBB crossing and CNS therapy. Niewoehner J, Bohrmann B, Collin L, et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 2014;81:49--60 Tosi G, Bortot B, Ruozi B, et al. Potential use of polymeric nanoparticles for drug delivery across the blood-brain barrier. Curr Med Chem 2013;20:2212--25 Vilella A, Tosi G, Grabrucker AM, et al. Insight on the fate of CNS-targeted nanoparticles. Part I: Rab5-dependent cell-specific uptake and distribution. J Control Rel 2014;174:195--201 Good paper on the fate of nanomedicine inside the CNS.
Expert Opin. Drug Deliv. (2015) 12(7)
12.
Teli MK, Mutalik S, Rajanikant GK. Nanotechnology and nanomedicine: going small means aiming big. Curr Pharm Des 2010;16:1882--92
13.
Pautler M, Brenner S. Nanomedicine: promises and challenges for the future of public health. Int J Nanomedicine 2010;5:803--9
14.
Murday JS, Siegel RW, Stein J, et al. Translational nanomedicine: status assessment and opportunities. Nanomedicine 2009;5:251--73 Very good review on the analysis of the transalatability of nanomedicine with clear assessment of limits and advantages.
..
15.
Wagner V, Dullaart A, Bock AK, et al. The emerging nanomedicine landscape. Nature Biotech 2006;24:1211--17
Affiliation
Giovanni Tosi†, Maria Angela Vandelli, Flavio Forni & Barbara Ruozi † Author for correspondence Professor, University of Modena and Reggio Emilia, Department of Life Sciences, Nanomedicine Group, 41124, Modena, Italy Tel: +39 059 2055128; Fax: +39 059 2055131; E-mail: [email protected]
