Drug Discovery Today Volume 00, Number 00 April 2015
EDITORIAL
editorial Charles Oo Jui-Chen Tsai H. Danny Kao
There is no better time than the present: nanotechnology as a disruptive innovation for drug development For years, the pharmaceutical industry has been lamenting the slowness and difficulty of drug approval by the US Food and Drug Administration (FDA). However, 2014 was a banner year, with the approvals of 41 new molecular entities (NMEs). A similar trend was seen in 2012, with 39 new approvals. Ever since the formation of the FDA, these records have been superseded only in 1996 (53 approvals). Nevertheless, 1996 is regarded as an abnormality because of previous years of application backlogs and the overhaul of the approval process.
1359-6446/ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2015.03.013
The completion of the Human Genome Project approximately a decade ago represented a key step forward for science. However, decoding of human DNA is insufficient to provide the immediate relief for many human illnesses. Confounding factors, including gene mutations and epigenetic modifications, disease heterogeneity, mitochondrial participation, and immune response, need to be addressed. Unless a drug is geared directly towards reversing a specific aberration of a disease, a partial remedy or a symptomatic treatment without accounting for these factors might not be shown to be effective phenotypically. Using nanoparticles (1–100 nm or up to 1000 nm) is not new, but their benefits as drug carriers have been revealed only recently. Unlike conventional drugs, nanoparticles can provide unique structural, optical, and magnetic properties, and enable multifunctional drug encapsulations and surface modifications that are conducive for drug targeting [1]. Although the chemistry, manufacturing, and control (CMC) of nanomedicines can be intricate, the ability to confer these strategies in a noninvasive way is considerable. Given that nanomedicines are unique in safety and efficacy, a framework of global regulatory requirements has been emerging. The FDA and European Medicines Agency (EMA) have formulated draft guidances [2,3], in addition to recent strategies developed in Taiwan [4]. The forefront of nanotechnology utilization is in oncology [5]. Until now, the mainstay of cancer treatment has been chemotherapy. Traditional cancer chemotherapy is based on the principle of cytotoxicity, which gravely affects fast-growing cells, leading to substantial toxicity. Even with the use of combination therapies, the efficacies are often short lived because of the emergence of drug resistant and relapse. We now know that tumor cells are capable of evading host immune surveillance, finding sanctuaries in nonphagocytic sites (such as within host cells and in deep compartments, such as the brain or bone marrow), or surviving as cancer stem cells. It is thought that quiescent cancer stem cells are the main culprits of cancer relapse, because these cells could revert back to express cancer symptomatology at an opportune time. The advantages of using nanoparticles in cancer are encouraging, primarily because of enhanced permeability and retention effects and improved intracellular drug delivery. Nanotechnology can substantially enhance the use of biomarkers to guide diagnosis
www.drugdiscoverytoday.com 1 Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
DRUDIS-1602; No of Pages 3 EDITORIAL
and treatment. Selective eradication of pathogenic stem cells will also be possible with the use of nanomedicines. Major factors that can be mitigated by nanomedicines as illustrated in cancer and other diseases are elaborated below.
Drug Discovery Today Volume 00, Number 00 April 2015
cells, the disruption of mitochondrial integrity to attain programmed cell death is crucial for achieving treatment efficacy and avoiding drug resistance [7].
Immune response Gene mutations and epigenetic modifications
Editorial
Large-scale sequencing of coding DNA (2% of the whole genome) has shown that direct gene mutations could be associated with the genesis of common cancers at the stage of tumor initiation. Conversely, patients seeking treatment generally present with more advanced stages, where additional mutations and modifications have occurred. Therefore, other than at the initial stage, few specific mutations are tightly associated with one cancer type. To discriminate from general gene mutations, epigenetic modifications of the remaining genomes are defined here as: ‘the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in coding DNA sequence’ [6]. Epigenetic modifications generally comprise histone variants, post-translational modifications of amino acids on the amino-terminal tail of histones, and covalent modifications of DNA bases, which are potentially reversible and can occur rapidly. Nanoparticles functioning at a molecular level will be a better arsenal to alleviate these aberrations.
Tumor heterogeneity Tumors, especially solid tumors, are pathophysiologically heterogeneous. For example, some parts of tumors are not vascularized and do not exhibit enhanced permeability and retention effects. Given the wide intratumoral microenvironment and interpatient heterogeneity, cancer treatments and diagnoses have variable success. In general, patients with cancer are dosed empirically based on body surface area, and treatment efficacy and toxicity are monitored with a delay via imaging (CT, MRI, ultrasound, X-ray, or endoscopy and/or laparoscopy). Until recently, real-time feedback was rarely provided to determine the dose of a drug, intratumoral drug concentration, or therapeutic efficacy. Recently, personalized medicine has become realizable with the advances in nanotechnology. Continuous monitoring during and after cancer treatment to signal remission and relapse, or even trigger drug delivery is now achievable using implantable devices.
Mitochondrial participation The importance of mitochondria is beginning to be recognized in cell integrity and survival. Mitochondria, the ‘energy factories’ of a cell, are involved in energy production, cellular metabolism, and apoptosis [7]. Mitochondrial dysfunctions are thought to be implicated in various diseases, including cancer, atherosclerosis, diabetes, cardiovascular diseases, and the neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis). However, because of the high complexity of mitochondria, drug availability within the active site remains a challenge. Targeting mitochondria is now attainable using hybrid nanomedicines with properties such as biodegradability, magnetization, and fluorescence [8]. For diseased
2
The complex regulations of the immune system, coupled with the systemic adverse effects of traditional drug therapies, have presented major hurdles for the development of anticancer drugs. It has been demonstrated that tumor cells exploit multiple redundant signaling pathways to block immune response. Therefore, suppressing a single pathway will be unlikely to have a major therapeutic benefit. In addition, immune response can be regarded as both a cause and cure of diseases. It is known that, after an acute or chronic insult by an external or internal factor, the body will attempt to ameliorate the disruption by activating the immune response. Although the need for repair is desirable, such an attempt can worsen the condition, causing more tissue destruction and widespread inflammation. Therefore, the ability to selectively suppress excessive inflammation while allowing for repair is the crux of therapy. Recent advances in our basic understanding of the role of the innate and adaptive immune systems have provided new insights into the central roles of the excesses of cytokines, tumor necrosis factor, and activated immune cells [9]. For cancer, the increased understanding of tumor immunology has led to the development of specific immunotherapies. In highly mutated and modified cancers, immunotherapies can provide the ultimate hope, superseding those of chemotherapies, because the body immune response can evolve as rapidly as in cancer cells. Moreover, a better understanding of the immune response in cancer could have far-reaching implications in other illnesses, such as neuroinflammatory disorders, traumatic brain injuries, and neurodegenerative and autoimmune diseases, where the immune response has a critical role in tissue damage, inflammation, and treatment outcome.
Concluding remarks The dawn of a new era has arrived. With the use of nanotechnology, the delivery of a single drug or multiple drug therapies that have the potential to revolutionize drug development is now feasible. Currently, there are several nanotechnology-enabled diagnostic and therapeutic agents undergoing preclinical and clinical tests, and a few have already been approved by the regulatory agencies. With a recent bipartisan proposal by the US House Energy and Commerce Committee (which oversees the FDA) to expedite drug development, the best is yet to come. References 1 Ventola, C.L. (2012) The nanomedicine revolution: Part 1: emerging concepts. Pharmacol. Ther. 37, 512–525 2 Hamburg, M.A. (2012) Science and regulation, FDA’s approach to regulation of products of nanotechnology. Science 336, 299–300 3 Ehmann, F. et al. (2013) Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine 8, 849–856 4 Guo, J. et al. (2014) Development of Taiwan’s strategies for regulating nanotechnology-based pharmaceuticals harmonized with international considerations. Inter. J. Nanomed. 9, 4773–4783
www.drugdiscoverytoday.com Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
DRUDIS-1602; No of Pages 3 Drug Discovery Today Volume 00, Number 00 April 2015
Charles Oo graduated with a B.Sc. in Pharmacy from the Universiti Sains Malaysia, a Pharm.D. from the Wayne State University, and a Ph.D. in Clinical and Experimental Therapeutics from the University of Kentucky. He is broadly experienced in basic and clinical research and has been involved in global drug development from all Phases including in Medical Affairs. He has worked in Asubio Pharmaceuticals Inc, a subsidiary of DaiiChi Sankyo, Sanofi-aventis, Hoffmann La Roche, and Roche Laboratory Inc. He has practiced pharmacy in the United States, and is a Diplomat of the American Board of applied Clinical Pharmacology, a Fellow of the College of Clinical Pharmacology, a reviewer of a number of journals, and has involved in peer-reviewed publications, abstracts, and public presentations. Jui-Chen Tsai graduated with a B.Sc. in Pharmacy from the National Taiwan University, a M.S. and a Ph.D. in Pharmaceutics from the University of Michigan. She is currently a professor of School of Pharmacy and the Institute of Clinical Pharmacy and Pharmaceutical Sciences at the National Cheng Kung University, and has served as the Chair of Institute of Clinical Pharmacy and the Director of
Pharmacy Department of the University Hospital in the past. She is a registered pharmacist and has worked as a hospital pharmacist, a drug analyst and a research scientist. Her research interest includes percutaneous absorption, drug delivery systems, cosmeceuticals and regulatory sciences. She has published broadly in peer-review journals, books and chapters and has filed a patent. H. Danny Kao received his B.Sc. in Pharmacy from the National Taiwan University, M.S. from St. John’s University, a Ph.D. from the University of Kentucky, and J.D. from the Touro College, New York. He is a registered patent attorney, a member of the Regulatory Working Group of Cross Company Abuse Liability Consortium, and has been awarded a fellowship from the Pharmaceutical Research and Manufacturers of America. He has an expertise in opioid drug formulations and delivery systems, and has more than 20 issued and pending patents. He currently works as the chief IP counsel and senior vice president of Relmada Therapeutics Inc, and has previously worked for Endo and DuPont Pharma.
Charles Oo1* Jui-Chen Tsai2 H. Danny Kao3 1
Morris Plains, NJ 07950, USA School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan 3 Relmada Therapeutics, Inc., New York, NY 10036, USA 2
*Corresponding author. emails: [email protected], [email protected]
www.drugdiscoverytoday.com 3 Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
Editorial
5 Ventola, C.L. (2012) The nanomedicine revolution: Part 2: current and future clinical applications. Pharmacol. Ther. 37, 582–591 6 Dupont, C. et al. (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin. Reprod. Med. 27, 351–357 7 Doss, C.G.P. et al. (2013) Disruption of mitochondrial complexes in cancer stem cells through nano-based drug delivery: a promising mitochondrial medicine. Cell Biochem. Biophys. 67, 1075–1079 8 Pathak, R.K. et al. (2014) Targeted nanoparticles in mitochondrial medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. Published October 27, 2014. http://dx.doi. org/10.1002/wnan.1305 9 Moon, J.J. et al. (2012) Engineering nano- and microparticles to tune immunity. Adv. Mater. 24, 3724–3746
EDITORIAL
EDITORIAL
editorial Charles Oo Jui-Chen Tsai H. Danny Kao
There is no better time than the present: nanotechnology as a disruptive innovation for drug development For years, the pharmaceutical industry has been lamenting the slowness and difficulty of drug approval by the US Food and Drug Administration (FDA). However, 2014 was a banner year, with the approvals of 41 new molecular entities (NMEs). A similar trend was seen in 2012, with 39 new approvals. Ever since the formation of the FDA, these records have been superseded only in 1996 (53 approvals). Nevertheless, 1996 is regarded as an abnormality because of previous years of application backlogs and the overhaul of the approval process.
1359-6446/ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2015.03.013
The completion of the Human Genome Project approximately a decade ago represented a key step forward for science. However, decoding of human DNA is insufficient to provide the immediate relief for many human illnesses. Confounding factors, including gene mutations and epigenetic modifications, disease heterogeneity, mitochondrial participation, and immune response, need to be addressed. Unless a drug is geared directly towards reversing a specific aberration of a disease, a partial remedy or a symptomatic treatment without accounting for these factors might not be shown to be effective phenotypically. Using nanoparticles (1–100 nm or up to 1000 nm) is not new, but their benefits as drug carriers have been revealed only recently. Unlike conventional drugs, nanoparticles can provide unique structural, optical, and magnetic properties, and enable multifunctional drug encapsulations and surface modifications that are conducive for drug targeting [1]. Although the chemistry, manufacturing, and control (CMC) of nanomedicines can be intricate, the ability to confer these strategies in a noninvasive way is considerable. Given that nanomedicines are unique in safety and efficacy, a framework of global regulatory requirements has been emerging. The FDA and European Medicines Agency (EMA) have formulated draft guidances [2,3], in addition to recent strategies developed in Taiwan [4]. The forefront of nanotechnology utilization is in oncology [5]. Until now, the mainstay of cancer treatment has been chemotherapy. Traditional cancer chemotherapy is based on the principle of cytotoxicity, which gravely affects fast-growing cells, leading to substantial toxicity. Even with the use of combination therapies, the efficacies are often short lived because of the emergence of drug resistant and relapse. We now know that tumor cells are capable of evading host immune surveillance, finding sanctuaries in nonphagocytic sites (such as within host cells and in deep compartments, such as the brain or bone marrow), or surviving as cancer stem cells. It is thought that quiescent cancer stem cells are the main culprits of cancer relapse, because these cells could revert back to express cancer symptomatology at an opportune time. The advantages of using nanoparticles in cancer are encouraging, primarily because of enhanced permeability and retention effects and improved intracellular drug delivery. Nanotechnology can substantially enhance the use of biomarkers to guide diagnosis
www.drugdiscoverytoday.com 1 Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
DRUDIS-1602; No of Pages 3 EDITORIAL
and treatment. Selective eradication of pathogenic stem cells will also be possible with the use of nanomedicines. Major factors that can be mitigated by nanomedicines as illustrated in cancer and other diseases are elaborated below.
Drug Discovery Today Volume 00, Number 00 April 2015
cells, the disruption of mitochondrial integrity to attain programmed cell death is crucial for achieving treatment efficacy and avoiding drug resistance [7].
Immune response Gene mutations and epigenetic modifications
Editorial
Large-scale sequencing of coding DNA (2% of the whole genome) has shown that direct gene mutations could be associated with the genesis of common cancers at the stage of tumor initiation. Conversely, patients seeking treatment generally present with more advanced stages, where additional mutations and modifications have occurred. Therefore, other than at the initial stage, few specific mutations are tightly associated with one cancer type. To discriminate from general gene mutations, epigenetic modifications of the remaining genomes are defined here as: ‘the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in coding DNA sequence’ [6]. Epigenetic modifications generally comprise histone variants, post-translational modifications of amino acids on the amino-terminal tail of histones, and covalent modifications of DNA bases, which are potentially reversible and can occur rapidly. Nanoparticles functioning at a molecular level will be a better arsenal to alleviate these aberrations.
Tumor heterogeneity Tumors, especially solid tumors, are pathophysiologically heterogeneous. For example, some parts of tumors are not vascularized and do not exhibit enhanced permeability and retention effects. Given the wide intratumoral microenvironment and interpatient heterogeneity, cancer treatments and diagnoses have variable success. In general, patients with cancer are dosed empirically based on body surface area, and treatment efficacy and toxicity are monitored with a delay via imaging (CT, MRI, ultrasound, X-ray, or endoscopy and/or laparoscopy). Until recently, real-time feedback was rarely provided to determine the dose of a drug, intratumoral drug concentration, or therapeutic efficacy. Recently, personalized medicine has become realizable with the advances in nanotechnology. Continuous monitoring during and after cancer treatment to signal remission and relapse, or even trigger drug delivery is now achievable using implantable devices.
Mitochondrial participation The importance of mitochondria is beginning to be recognized in cell integrity and survival. Mitochondria, the ‘energy factories’ of a cell, are involved in energy production, cellular metabolism, and apoptosis [7]. Mitochondrial dysfunctions are thought to be implicated in various diseases, including cancer, atherosclerosis, diabetes, cardiovascular diseases, and the neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis). However, because of the high complexity of mitochondria, drug availability within the active site remains a challenge. Targeting mitochondria is now attainable using hybrid nanomedicines with properties such as biodegradability, magnetization, and fluorescence [8]. For diseased
2
The complex regulations of the immune system, coupled with the systemic adverse effects of traditional drug therapies, have presented major hurdles for the development of anticancer drugs. It has been demonstrated that tumor cells exploit multiple redundant signaling pathways to block immune response. Therefore, suppressing a single pathway will be unlikely to have a major therapeutic benefit. In addition, immune response can be regarded as both a cause and cure of diseases. It is known that, after an acute or chronic insult by an external or internal factor, the body will attempt to ameliorate the disruption by activating the immune response. Although the need for repair is desirable, such an attempt can worsen the condition, causing more tissue destruction and widespread inflammation. Therefore, the ability to selectively suppress excessive inflammation while allowing for repair is the crux of therapy. Recent advances in our basic understanding of the role of the innate and adaptive immune systems have provided new insights into the central roles of the excesses of cytokines, tumor necrosis factor, and activated immune cells [9]. For cancer, the increased understanding of tumor immunology has led to the development of specific immunotherapies. In highly mutated and modified cancers, immunotherapies can provide the ultimate hope, superseding those of chemotherapies, because the body immune response can evolve as rapidly as in cancer cells. Moreover, a better understanding of the immune response in cancer could have far-reaching implications in other illnesses, such as neuroinflammatory disorders, traumatic brain injuries, and neurodegenerative and autoimmune diseases, where the immune response has a critical role in tissue damage, inflammation, and treatment outcome.
Concluding remarks The dawn of a new era has arrived. With the use of nanotechnology, the delivery of a single drug or multiple drug therapies that have the potential to revolutionize drug development is now feasible. Currently, there are several nanotechnology-enabled diagnostic and therapeutic agents undergoing preclinical and clinical tests, and a few have already been approved by the regulatory agencies. With a recent bipartisan proposal by the US House Energy and Commerce Committee (which oversees the FDA) to expedite drug development, the best is yet to come. References 1 Ventola, C.L. (2012) The nanomedicine revolution: Part 1: emerging concepts. Pharmacol. Ther. 37, 512–525 2 Hamburg, M.A. (2012) Science and regulation, FDA’s approach to regulation of products of nanotechnology. Science 336, 299–300 3 Ehmann, F. et al. (2013) Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine 8, 849–856 4 Guo, J. et al. (2014) Development of Taiwan’s strategies for regulating nanotechnology-based pharmaceuticals harmonized with international considerations. Inter. J. Nanomed. 9, 4773–4783
www.drugdiscoverytoday.com Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
DRUDIS-1602; No of Pages 3 Drug Discovery Today Volume 00, Number 00 April 2015
Charles Oo graduated with a B.Sc. in Pharmacy from the Universiti Sains Malaysia, a Pharm.D. from the Wayne State University, and a Ph.D. in Clinical and Experimental Therapeutics from the University of Kentucky. He is broadly experienced in basic and clinical research and has been involved in global drug development from all Phases including in Medical Affairs. He has worked in Asubio Pharmaceuticals Inc, a subsidiary of DaiiChi Sankyo, Sanofi-aventis, Hoffmann La Roche, and Roche Laboratory Inc. He has practiced pharmacy in the United States, and is a Diplomat of the American Board of applied Clinical Pharmacology, a Fellow of the College of Clinical Pharmacology, a reviewer of a number of journals, and has involved in peer-reviewed publications, abstracts, and public presentations. Jui-Chen Tsai graduated with a B.Sc. in Pharmacy from the National Taiwan University, a M.S. and a Ph.D. in Pharmaceutics from the University of Michigan. She is currently a professor of School of Pharmacy and the Institute of Clinical Pharmacy and Pharmaceutical Sciences at the National Cheng Kung University, and has served as the Chair of Institute of Clinical Pharmacy and the Director of
Pharmacy Department of the University Hospital in the past. She is a registered pharmacist and has worked as a hospital pharmacist, a drug analyst and a research scientist. Her research interest includes percutaneous absorption, drug delivery systems, cosmeceuticals and regulatory sciences. She has published broadly in peer-review journals, books and chapters and has filed a patent. H. Danny Kao received his B.Sc. in Pharmacy from the National Taiwan University, M.S. from St. John’s University, a Ph.D. from the University of Kentucky, and J.D. from the Touro College, New York. He is a registered patent attorney, a member of the Regulatory Working Group of Cross Company Abuse Liability Consortium, and has been awarded a fellowship from the Pharmaceutical Research and Manufacturers of America. He has an expertise in opioid drug formulations and delivery systems, and has more than 20 issued and pending patents. He currently works as the chief IP counsel and senior vice president of Relmada Therapeutics Inc, and has previously worked for Endo and DuPont Pharma.
Charles Oo1* Jui-Chen Tsai2 H. Danny Kao3 1
Morris Plains, NJ 07950, USA School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan 3 Relmada Therapeutics, Inc., New York, NY 10036, USA 2
*Corresponding author. emails: [email protected], [email protected]
www.drugdiscoverytoday.com 3 Please cite this article in press as: Oo, C. et al. There is no better time than the present: nanotechnology as a disruptive innovation for drug development, Drug Discov Today (2015), http:// dx.doi.org/10.1016/j.drudis.2015.03.013
Editorial
5 Ventola, C.L. (2012) The nanomedicine revolution: Part 2: current and future clinical applications. Pharmacol. Ther. 37, 582–591 6 Dupont, C. et al. (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin. Reprod. Med. 27, 351–357 7 Doss, C.G.P. et al. (2013) Disruption of mitochondrial complexes in cancer stem cells through nano-based drug delivery: a promising mitochondrial medicine. Cell Biochem. Biophys. 67, 1075–1079 8 Pathak, R.K. et al. (2014) Targeted nanoparticles in mitochondrial medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. Published October 27, 2014. http://dx.doi. org/10.1002/wnan.1305 9 Moon, J.J. et al. (2012) Engineering nano- and microparticles to tune immunity. Adv. Mater. 24, 3724–3746
EDITORIAL
