Research Highlights For reprint orders, please contact: [email protected]
Highlights from recent advances in nanomedicine
Nanocarrier Trojan horses could conquer barriers Evaluation of: 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 Release. 174, 195–201 (2014).
Poor penetration of therapeutics into blood–brain barrier (BBB) is mostly viewed as a confounding limiting factor for effective treatment [1] , against many CNS diseases, as well as cancer. Although it is uncertain what new delivery platforms will emerge as the most efficacious and useful, but it is certain that many new approaches are being investigated in an effort to increase effective therapeutics into brain. However, any attempt to develop new nanotherapeutics [2–4] for brain diseases must deal with a major vexing impediment of BBB; a real obstacle for therapeutics. In this elaborative research paper, Vilella et al. investigated in detail the glycopeptideengineered poly(d,l-lactide-co-glycolide (PLGA) nanoparticles (g7-NPs), an innovative study with the potential to address one of the biggest problems in modern neurobiology, how to effectively deliver enough of the right drug through a difficult-to-cross BBB, with minimum side effects. Other researchers are using the tools of physical science, from robotics to computer science, to explore more effective ways to overcome hitching barriers [5] . Indeed, the whole field is still evolving. Nevertheless, a potential advantage of a g7-delivery platform will be the use of combination therapeutic approaches [6,7] with antibody therapeutics [8] and siRNA [9,10] , which hold great
10.2217/NNM.14.82 © 2014 Future Medicine Ltd
promise as a new class of therapeutics, and, if successful, could increase the potential range of therapeutic strategies. The field of drug delivery is a powerful concept in nanomedicine that is advancing rapidly. New advanced multifunctional ‘nanocarriers’ [3,9–12] with minutely controlled chemistry, size, surface charge and other properties can slip selectively into cancerous tissues or protect the drugs they carry from being destroyed before they reach their destination, are certainly on the horizon and bode well for a renaissance of interest in future nanomedicine. The goal has got to be to have a major advance to create clinically more sophisticated nanocarrier Trojan horses that sneak any thing from neural growth factors to therapeutic nucleic acid constructs into the brain.
Farooq A Shiekh Department of Basic Medical Sciences, Avalon University School of Medicine, Curacao, Netherlands Antilles [email protected]
siRNA nanotherapeutics a real promise Evaluation of: Dong Y, Love KT, Dorkin JR et al. Lipopeptide nanomparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc. Natl Acad. Sci. USA 111(11), 3955–3960 (2014).
The most promising application of nanotherapeutics is gene silencing, in which small bits of RNA are deployed to shut down some key disease causing genes through a process known as RNAi. siRNA therapy has the potential to offer new biologically based medicines [13] . Nevertheless, without a good delivery vehicle, the efficient, selective and safe delivery of siRNA to the specific drug targets is still a major challenge to the broad application of siRNA therapeutics [14,15] .
Nanomedicine (2014) 9(9), 1287–1289
part of
ISSN 1743-5889
1287
News & Views Research Highlights However, a new study by Dong et al. demonstrates that they have been able to successfully design a ‘lead’ modular form of lipopeptide nanoparticle designated as cKK-E12 LPNs – an advancement that is expected to lead the most efficacious and selective nonviral siRNA delivery for gene silencing in target cells. For example, in vivo administration of these siRNA-lipopeptide particles in mice showed the most potent delivery to hepatocytes (ED50 ∼0.002 mg/kg for FVII silencing) over nontarget cell types. The potential benefit of these increasing efforts will be to keep toxic drugs out of healthy tissues, as one of the greatest uses of future nanomedicine. Unfortunately, the profound limiting factor with the use of antisense oligonucleotides in humans is their intracellular delivery to particular cell types and organs that express the target gene and the potential of carrying effective number of siRNA molecules per nanocarrier, making the siRNA therapy a major clinical challenge [15] . Recently, several of the multifunctional delivery platforms [16–18] have been combined with siRNA to improve their delivery in animal models [19,20] , in order to provide an exciting new class of siRNA delivery with promising clinical translational potential. However, by taking advantage of the natural architecture of apolipoproteins and the advances of lipopeptide nanoparticles [21] , the highlight of this study is the key role of apo E in mediating potent and selective delivery of siRNA nanotherapeutics through a noncanonical pathway by which they suppose to use dynamin-dependent macropinocytosis similar to the entry mechanism of bluetongue virus-1. Significantly, this delivery mechanism would enable researchers to improve the design to advance siRNA delivery platform that accompanies an escort intelligent enough to evade destruction and minimize toxicity. When taken together, the data presented by the authors provide the first evidence for efficacious and selective, but nonviral siRNA delivery for gene silencing. siRNA holds great promise as a potential new class of targeted therapeutics with the ability to treat even complex tumors that have thus far been resistant to the available therapies. These advances point to a future where siRNAs are delivered to the specific target where they are needed and at the required levels they are required, with maximum benefit to patients. Next-generation nanoprobes Evaluation of: Actis P, Tokar S, Clausmeyer J et al. Electrochemical nanoprobes for single-cell analysis. ACS Nano 8(1), 875–884 (2014).
Advances in nanodevices are also proving useful to biologists who are interested in focusing on single
1288
Nanomedicine (2014) 9(9)
molecules. Sensors and probes have been miniatured, but there is also an effort to miniaturize and integrate sample preprocessing with analytic detection. Nanopillars, nanopipette probes and multifunctional carbon nanoelectrodes equipped with scanning ion conductance microscopy (SICM) or simultaneous SICM-scanning electrochemical microscopy (SECM) imaging, allowing the investigator to follow in-cell events on camera with an astonishing level of detail [22–24] . However, measurement of clinically important analytical aspects of individual cells at the microand nano-scale has not been explored to their full potential. More recently Actis et al. have described the nanofabrication and tailoring of carbon nanoelectrodes for intracellular electrochemical recordings. The authors were sucessfully able to demonstrate the fabrication of disk-shaped nanoelectrodes whose radius could be precisely tuned within the size limit of 5–200 nm. In the past, it has been challenging to image nanoelectrodes smaller than 50 nm by scanning electron microscopy [25] . The great advantage of these nanoelectodes is that they are technically straightforward, yet analytically powerful, so could be further integrated into the multifunctional platform nanoprobes. The clinical implications of such electrodes for cell biology are huge and they could be the ideal singlecell surgical tools, thus could penetrate a single-cell either in intact tissues or in isolation to perform intracellular electrochemical measurements with high precision and notably a cell can withstand multiple penetrations for critical evaluations with minimal disruption to the biological milieu. For example, nanofabricated electrodes with platinum showed the ability to monitor oxygen consumption in neural cells with single-molecule sensitivity. Other newer nanofabrications are being investigated in an effort to help to perform real-time analytical measurements of melanoma and to check the status of reactive oxygen species in the mitochondrial respiration. The fruition of these efforts in the clinic is just now being realized with the introduction of these cutting-edge next-generation probes. Financial & competing interests disclosure The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
Research Highlights
References 1
Bhujbal SV, de VP, Niclou SP. Drug and cell encapsulation: alternative delivery options for the treatment of malignant brain tumors. Adv. Drug. Deliv. Rev. 67–68, 142–153 (2014).
2
Ding H, Sagar V, Agudelo M et al. Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation. Nanotechnology 25, 055101 (2014).
3
Choi HS. Nanoparticle assembly: building blocks for tumour delivery Nat. Nanotechnol. 9, 93–94 (2014).
4
Guo S, Miao L, Wang Y, Huang L. Unmodified drug used as a material to construct nanoparticles: delivery of cisplatin for enhanced anti-cancer therapy. J. Control. Release 174, 137–142 (2014).
5
Toumey C. Nanobots today. Nat. Nanotechnol. 8, 475–476 (2013).
6
Sun X, Vilar S, Tatonetti NP. High-throughput methods for combinatorial drug discovery. Sci. Transl. Med. 5, 205rv1 (2013).
7
Chow EK, Ho D. Cancer nanomedicine: from drug delivery to imaging Sci. Transl. Med. 5, 216rv4 (2013).
8
Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science 341, 1192–1198 (2013).
9
Deng ZJ, Morton SW, Ben-Akiva E, Dreaden EC, Shopsowitz KE, Hammond PT. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano 7, 9571–9584 (2013).
10
Shiekh FA. Targeted nanotherapeutics in cancer. Int. J. Nanomedicine 9(1), 1627–1628 (2014).
11
Chou LY, Zagorovsky K, Chan WC. DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination. Nat. Nanotechnol. 9, 148–155 (2014).
12
13
Tagalakis AD, Kenny GD. Bienemann AS et al. PEGylation improves the receptor-mediated transfection efficiency of peptide-targeted, self-assembling, anionic nanocomplexes. J. Control. Release 174, 177–187 (2014). Putnam D. Design and development of effective siRNA delivery vehicles. Proc. Natl Acad. Sci. USA 111(11), 3903–3904 (2014).
future science group
14
Bourzac K. Nanotechnology: carrying drugs. Nature 491, S58–S60 (2012).
15
Xue HY, Liu S, Wong HL. Nanotoxicity: a key obstacle to clinical translation of siRNA-based nanomedicine. Nanomedicine (Lond.) 9, 295–312 (2014).
16
Huang X, Pallaoro A, Braun GB et al. Modular plasmonic nanocarriers for efficient and targeted delivery of cancertherapeutic siRNA. Nano Lett. (2014).
17
Tan YF, Mundargi RC, Chen MH et al. Layer-by-layer nanoparticles as an efficient siRNA delivery vehicle for SPARC silencing. Small 10(9), 1790–1798 (2014).
18
Hartono SB, Yu M, Gu W et al. Synthesis of multi-functional large pore mesoporous silica nanoparticles as gene carriers. Nanotechnology 25, 055701 (2014).
19
Brock A, Krause S, Li H et al. Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. Sci. Transl. Med. 6, 217ra2 (2014).
20
Khatri N, Baradia D, Vhora I, Rathi M, Misra A. cRGD grafted liposomes containing inorganic nano-precipitate complexed siRNA for intracellular delivery in cancer cells. J. Control. Release 182, 45–57 (2014).
21
He W, Bennett MJ, Luistro L et al. Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability. Mol. Ther. 22, 359–370 (2014).
22
Yoon HJ, Kozminsky M, Nagrath S. Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS Nano 8, 1995–2017 (2014).
23
Wu Z, Lei H, Zhou T, Fan Y, Zhong Z. Fabrication and characterization of SiGe coaxial quantum wells on ordered Si nanopillars Nanotechnology 25, 055204 (2014).
24
Ivanov AP, Freedman KJ, Kim MJ, Albrecht T, Edel JB. High precision fabrication and positioning of nanoelectrodes in a nanopore. ACS Nano 8, 1940–1948 (2014).
25
Takahashi Y, Shevchuk AI, Novak P et al. Topographical and electrochemical nanoscale imaging of living cells using voltage-switching mode scanning electrochemical microscopy. Proc. Natl Acad. Sci. USA 109, 11540–11545 (2012).
www.futuremedicine.com
News & Views
1289
Highlights from recent advances in nanomedicine
Nanocarrier Trojan horses could conquer barriers Evaluation of: 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 Release. 174, 195–201 (2014).
Poor penetration of therapeutics into blood–brain barrier (BBB) is mostly viewed as a confounding limiting factor for effective treatment [1] , against many CNS diseases, as well as cancer. Although it is uncertain what new delivery platforms will emerge as the most efficacious and useful, but it is certain that many new approaches are being investigated in an effort to increase effective therapeutics into brain. However, any attempt to develop new nanotherapeutics [2–4] for brain diseases must deal with a major vexing impediment of BBB; a real obstacle for therapeutics. In this elaborative research paper, Vilella et al. investigated in detail the glycopeptideengineered poly(d,l-lactide-co-glycolide (PLGA) nanoparticles (g7-NPs), an innovative study with the potential to address one of the biggest problems in modern neurobiology, how to effectively deliver enough of the right drug through a difficult-to-cross BBB, with minimum side effects. Other researchers are using the tools of physical science, from robotics to computer science, to explore more effective ways to overcome hitching barriers [5] . Indeed, the whole field is still evolving. Nevertheless, a potential advantage of a g7-delivery platform will be the use of combination therapeutic approaches [6,7] with antibody therapeutics [8] and siRNA [9,10] , which hold great
10.2217/NNM.14.82 © 2014 Future Medicine Ltd
promise as a new class of therapeutics, and, if successful, could increase the potential range of therapeutic strategies. The field of drug delivery is a powerful concept in nanomedicine that is advancing rapidly. New advanced multifunctional ‘nanocarriers’ [3,9–12] with minutely controlled chemistry, size, surface charge and other properties can slip selectively into cancerous tissues or protect the drugs they carry from being destroyed before they reach their destination, are certainly on the horizon and bode well for a renaissance of interest in future nanomedicine. The goal has got to be to have a major advance to create clinically more sophisticated nanocarrier Trojan horses that sneak any thing from neural growth factors to therapeutic nucleic acid constructs into the brain.
Farooq A Shiekh Department of Basic Medical Sciences, Avalon University School of Medicine, Curacao, Netherlands Antilles [email protected]
siRNA nanotherapeutics a real promise Evaluation of: Dong Y, Love KT, Dorkin JR et al. Lipopeptide nanomparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc. Natl Acad. Sci. USA 111(11), 3955–3960 (2014).
The most promising application of nanotherapeutics is gene silencing, in which small bits of RNA are deployed to shut down some key disease causing genes through a process known as RNAi. siRNA therapy has the potential to offer new biologically based medicines [13] . Nevertheless, without a good delivery vehicle, the efficient, selective and safe delivery of siRNA to the specific drug targets is still a major challenge to the broad application of siRNA therapeutics [14,15] .
Nanomedicine (2014) 9(9), 1287–1289
part of
ISSN 1743-5889
1287
News & Views Research Highlights However, a new study by Dong et al. demonstrates that they have been able to successfully design a ‘lead’ modular form of lipopeptide nanoparticle designated as cKK-E12 LPNs – an advancement that is expected to lead the most efficacious and selective nonviral siRNA delivery for gene silencing in target cells. For example, in vivo administration of these siRNA-lipopeptide particles in mice showed the most potent delivery to hepatocytes (ED50 ∼0.002 mg/kg for FVII silencing) over nontarget cell types. The potential benefit of these increasing efforts will be to keep toxic drugs out of healthy tissues, as one of the greatest uses of future nanomedicine. Unfortunately, the profound limiting factor with the use of antisense oligonucleotides in humans is their intracellular delivery to particular cell types and organs that express the target gene and the potential of carrying effective number of siRNA molecules per nanocarrier, making the siRNA therapy a major clinical challenge [15] . Recently, several of the multifunctional delivery platforms [16–18] have been combined with siRNA to improve their delivery in animal models [19,20] , in order to provide an exciting new class of siRNA delivery with promising clinical translational potential. However, by taking advantage of the natural architecture of apolipoproteins and the advances of lipopeptide nanoparticles [21] , the highlight of this study is the key role of apo E in mediating potent and selective delivery of siRNA nanotherapeutics through a noncanonical pathway by which they suppose to use dynamin-dependent macropinocytosis similar to the entry mechanism of bluetongue virus-1. Significantly, this delivery mechanism would enable researchers to improve the design to advance siRNA delivery platform that accompanies an escort intelligent enough to evade destruction and minimize toxicity. When taken together, the data presented by the authors provide the first evidence for efficacious and selective, but nonviral siRNA delivery for gene silencing. siRNA holds great promise as a potential new class of targeted therapeutics with the ability to treat even complex tumors that have thus far been resistant to the available therapies. These advances point to a future where siRNAs are delivered to the specific target where they are needed and at the required levels they are required, with maximum benefit to patients. Next-generation nanoprobes Evaluation of: Actis P, Tokar S, Clausmeyer J et al. Electrochemical nanoprobes for single-cell analysis. ACS Nano 8(1), 875–884 (2014).
Advances in nanodevices are also proving useful to biologists who are interested in focusing on single
1288
Nanomedicine (2014) 9(9)
molecules. Sensors and probes have been miniatured, but there is also an effort to miniaturize and integrate sample preprocessing with analytic detection. Nanopillars, nanopipette probes and multifunctional carbon nanoelectrodes equipped with scanning ion conductance microscopy (SICM) or simultaneous SICM-scanning electrochemical microscopy (SECM) imaging, allowing the investigator to follow in-cell events on camera with an astonishing level of detail [22–24] . However, measurement of clinically important analytical aspects of individual cells at the microand nano-scale has not been explored to their full potential. More recently Actis et al. have described the nanofabrication and tailoring of carbon nanoelectrodes for intracellular electrochemical recordings. The authors were sucessfully able to demonstrate the fabrication of disk-shaped nanoelectrodes whose radius could be precisely tuned within the size limit of 5–200 nm. In the past, it has been challenging to image nanoelectrodes smaller than 50 nm by scanning electron microscopy [25] . The great advantage of these nanoelectodes is that they are technically straightforward, yet analytically powerful, so could be further integrated into the multifunctional platform nanoprobes. The clinical implications of such electrodes for cell biology are huge and they could be the ideal singlecell surgical tools, thus could penetrate a single-cell either in intact tissues or in isolation to perform intracellular electrochemical measurements with high precision and notably a cell can withstand multiple penetrations for critical evaluations with minimal disruption to the biological milieu. For example, nanofabricated electrodes with platinum showed the ability to monitor oxygen consumption in neural cells with single-molecule sensitivity. Other newer nanofabrications are being investigated in an effort to help to perform real-time analytical measurements of melanoma and to check the status of reactive oxygen species in the mitochondrial respiration. The fruition of these efforts in the clinic is just now being realized with the introduction of these cutting-edge next-generation probes. Financial & competing interests disclosure The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
Research Highlights
References 1
Bhujbal SV, de VP, Niclou SP. Drug and cell encapsulation: alternative delivery options for the treatment of malignant brain tumors. Adv. Drug. Deliv. Rev. 67–68, 142–153 (2014).
2
Ding H, Sagar V, Agudelo M et al. Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation. Nanotechnology 25, 055101 (2014).
3
Choi HS. Nanoparticle assembly: building blocks for tumour delivery Nat. Nanotechnol. 9, 93–94 (2014).
4
Guo S, Miao L, Wang Y, Huang L. Unmodified drug used as a material to construct nanoparticles: delivery of cisplatin for enhanced anti-cancer therapy. J. Control. Release 174, 137–142 (2014).
5
Toumey C. Nanobots today. Nat. Nanotechnol. 8, 475–476 (2013).
6
Sun X, Vilar S, Tatonetti NP. High-throughput methods for combinatorial drug discovery. Sci. Transl. Med. 5, 205rv1 (2013).
7
Chow EK, Ho D. Cancer nanomedicine: from drug delivery to imaging Sci. Transl. Med. 5, 216rv4 (2013).
8
Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science 341, 1192–1198 (2013).
9
Deng ZJ, Morton SW, Ben-Akiva E, Dreaden EC, Shopsowitz KE, Hammond PT. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano 7, 9571–9584 (2013).
10
Shiekh FA. Targeted nanotherapeutics in cancer. Int. J. Nanomedicine 9(1), 1627–1628 (2014).
11
Chou LY, Zagorovsky K, Chan WC. DNA assembly of nanoparticle superstructures for controlled biological delivery and elimination. Nat. Nanotechnol. 9, 148–155 (2014).
12
13
Tagalakis AD, Kenny GD. Bienemann AS et al. PEGylation improves the receptor-mediated transfection efficiency of peptide-targeted, self-assembling, anionic nanocomplexes. J. Control. Release 174, 177–187 (2014). Putnam D. Design and development of effective siRNA delivery vehicles. Proc. Natl Acad. Sci. USA 111(11), 3903–3904 (2014).
future science group
14
Bourzac K. Nanotechnology: carrying drugs. Nature 491, S58–S60 (2012).
15
Xue HY, Liu S, Wong HL. Nanotoxicity: a key obstacle to clinical translation of siRNA-based nanomedicine. Nanomedicine (Lond.) 9, 295–312 (2014).
16
Huang X, Pallaoro A, Braun GB et al. Modular plasmonic nanocarriers for efficient and targeted delivery of cancertherapeutic siRNA. Nano Lett. (2014).
17
Tan YF, Mundargi RC, Chen MH et al. Layer-by-layer nanoparticles as an efficient siRNA delivery vehicle for SPARC silencing. Small 10(9), 1790–1798 (2014).
18
Hartono SB, Yu M, Gu W et al. Synthesis of multi-functional large pore mesoporous silica nanoparticles as gene carriers. Nanotechnology 25, 055701 (2014).
19
Brock A, Krause S, Li H et al. Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. Sci. Transl. Med. 6, 217ra2 (2014).
20
Khatri N, Baradia D, Vhora I, Rathi M, Misra A. cRGD grafted liposomes containing inorganic nano-precipitate complexed siRNA for intracellular delivery in cancer cells. J. Control. Release 182, 45–57 (2014).
21
He W, Bennett MJ, Luistro L et al. Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability. Mol. Ther. 22, 359–370 (2014).
22
Yoon HJ, Kozminsky M, Nagrath S. Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS Nano 8, 1995–2017 (2014).
23
Wu Z, Lei H, Zhou T, Fan Y, Zhong Z. Fabrication and characterization of SiGe coaxial quantum wells on ordered Si nanopillars Nanotechnology 25, 055204 (2014).
24
Ivanov AP, Freedman KJ, Kim MJ, Albrecht T, Edel JB. High precision fabrication and positioning of nanoelectrodes in a nanopore. ACS Nano 8, 1940–1948 (2014).
25
Takahashi Y, Shevchuk AI, Novak P et al. Topographical and electrochemical nanoscale imaging of living cells using voltage-switching mode scanning electrochemical microscopy. Proc. Natl Acad. Sci. USA 109, 11540–11545 (2012).
www.futuremedicine.com
News & Views
1289
