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Advanced Drug Delivery Reviews (v.64, #1)
Pulmonary delivery of therapeutic siRNA
by Jenny Ka-Wing Lam; Wanling Liang; Hak-Kim Chan (pp. 1-15).
Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various lung diseases. Once the RNA molecules have successfully entered the target cells, they could inhibit the expression of specific gene sequence through RNA interference (RNAi) mechanism and generate therapeutic effects. The biggest obstacle to translating siRNA therapy from the laboratories into the clinics is delivery. An ideal delivery agent should protect the siRNA from enzymatic degradation, facilitate cellular uptake and promote endosomal escape inside the cells, with negligible toxicity. Lung targeting could be achieved by systemic delivery or pulmonary delivery. The latter route of administration could potentially enhance siRNA retention in the lungs and reduce systemic toxic effects. However the presence of mucus, the mucociliary clearance actions and the high degree branching of the airways present major barriers to targeted pulmonary delivery. The delivery systems need to be designed carefully in order to maximize the siRNA deposition to the diseased area of the airways. In most of the pulmonary siRNA therapy studies in vivo, siRNA was delivered either intratracheally or intranasally. Very limited work was done on the formulation of siRNA for inhalation which is believed to be the direction for future development. This review focuses on the latest development of pulmonary delivery of siRNA for the treatment of various lung diseases.Display Omitted
Keywords: siRNA delivery; Lung; Inhalation; Aerosol; Non-viral
Pulmonary delivery of therapeutic siRNA
by Jenny Ka-Wing Lam; Wanling Liang; Hak-Kim Chan (pp. 1-15).
Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various lung diseases. Once the RNA molecules have successfully entered the target cells, they could inhibit the expression of specific gene sequence through RNA interference (RNAi) mechanism and generate therapeutic effects. The biggest obstacle to translating siRNA therapy from the laboratories into the clinics is delivery. An ideal delivery agent should protect the siRNA from enzymatic degradation, facilitate cellular uptake and promote endosomal escape inside the cells, with negligible toxicity. Lung targeting could be achieved by systemic delivery or pulmonary delivery. The latter route of administration could potentially enhance siRNA retention in the lungs and reduce systemic toxic effects. However the presence of mucus, the mucociliary clearance actions and the high degree branching of the airways present major barriers to targeted pulmonary delivery. The delivery systems need to be designed carefully in order to maximize the siRNA deposition to the diseased area of the airways. In most of the pulmonary siRNA therapy studies in vivo, siRNA was delivered either intratracheally or intranasally. Very limited work was done on the formulation of siRNA for inhalation which is believed to be the direction for future development. This review focuses on the latest development of pulmonary delivery of siRNA for the treatment of various lung diseases.Display Omitted
Keywords: siRNA delivery; Lung; Inhalation; Aerosol; Non-viral
New developments and opportunities in oral mucosal drug delivery for local and systemic disease
by Vanessa Hearnden; Vidya Sankar; Katrusha Hull; Danica Vidović Juras; Martin Greenberg; A. Ross Kerr; Peter B. Lockhart; Lauren L. Patton; Stephen Porter; Martin H. Thornhill (pp. 16-28).
The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.Display Omitted
Keywords: Abbreviations; GI; Gastro-intestinal; EPR; Enhanced Permeability and Retention; EGFR; Epidermal Growth Factor Receptor; COX-2; Cyclooxygenase 2; HSV; Herpes Simplex Virus; HIV; Human Immunodeficiency VirusOral mucosa; Drug delivery technology; Trans-mucosal; Local drug delivery; Formulations; Targeting; Mucoadhesives; Polymersomes
New developments and opportunities in oral mucosal drug delivery for local and systemic disease
by Vanessa Hearnden; Vidya Sankar; Katrusha Hull; Danica Vidović Juras; Martin Greenberg; A. Ross Kerr; Peter B. Lockhart; Lauren L. Patton; Stephen Porter; Martin H. Thornhill (pp. 16-28).
The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.Display Omitted
Keywords: Abbreviations; GI; Gastro-intestinal; EPR; Enhanced Permeability and Retention; EGFR; Epidermal Growth Factor Receptor; COX-2; Cyclooxygenase 2; HSV; Herpes Simplex Virus; HIV; Human Immunodeficiency VirusOral mucosa; Drug delivery technology; Trans-mucosal; Local drug delivery; Formulations; Targeting; Mucoadhesives; Polymersomes
Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor
by Yinghuan Li; Jie Wang; M. Guillaume Wientjes; Jessie L.-S. Au (pp. 29-39).
Advances in molecular medicines have led to identification of promising targets on cellular and molecular levels. These targets are located in extracellular and intracellular compartments. The latter include cytosol, nucleus, mitochondrion, Golgi apparatus and endoplasmic reticulum. This report gives an overview on the barriers to delivering nanomedicines to various target sites within a solid tumor, the experimental approaches to overcome such barriers, and the potential utility of nanotechnology.Display Omitted
Keywords: Abbreviations; CPP; cell penetrating peptides; ECM; extracellular matrix; EPR; enhanced permeability and retention; ER; endoplasmic reticulum; GAG; glycosaminoglycan; GALA; a 30 amino acid synthetic peptide with a glutamic acid–alanine–leucine–alanine repeat; IFP; interstitial fluid pressure; MVP; microvascular pressure; NLS; nuclear localization signal; NP; nanoparticulate carriers; NPC; nuclear pore complexes; PEG; polyethylene glycol; Pgp; P-glycoprotein; RES; reticuloendothelial system; RNAi; RNA interference; siRNA; small interfering RNANanotechnology; Nanoparticles; Liposomes; Drug delivery; Interstitial transport; Intracellular trafficking; Endosomal escape
Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor
by Yinghuan Li; Jie Wang; M. Guillaume Wientjes; Jessie L.-S. Au (pp. 29-39).
Advances in molecular medicines have led to identification of promising targets on cellular and molecular levels. These targets are located in extracellular and intracellular compartments. The latter include cytosol, nucleus, mitochondrion, Golgi apparatus and endoplasmic reticulum. This report gives an overview on the barriers to delivering nanomedicines to various target sites within a solid tumor, the experimental approaches to overcome such barriers, and the potential utility of nanotechnology.Display Omitted
Keywords: Abbreviations; CPP; cell penetrating peptides; ECM; extracellular matrix; EPR; enhanced permeability and retention; ER; endoplasmic reticulum; GAG; glycosaminoglycan; GALA; a 30 amino acid synthetic peptide with a glutamic acid–alanine–leucine–alanine repeat; IFP; interstitial fluid pressure; MVP; microvascular pressure; NLS; nuclear localization signal; NP; nanoparticulate carriers; NPC; nuclear pore complexes; PEG; polyethylene glycol; Pgp; P-glycoprotein; RES; reticuloendothelial system; RNAi; RNA interference; siRNA; small interfering RNANanotechnology; Nanoparticles; Liposomes; Drug delivery; Interstitial transport; Intracellular trafficking; Endosomal escape
Nonviral delivery of genetic medicine for therapeutic angiogenesis
by Hyun-Ji Park; Fan Yang; Seung-Woo Cho (pp. 40-52).
Genetic medicines that induce angiogenesis represent a promising strategy for the treatment of ischemic diseases. Many types of nonviral delivery systems have been tested as therapeutic angiogenesis agents. However, their delivery efficiency, and consequently therapeutic efficacy, remains to be further improved, as few of these technologies are being used in clinical applications. This article reviews the diverse nonviral gene delivery approaches that have been applied to the field of therapeutic angiogenesis, including plasmids, cationic polymers/lipids, scaffolds, and stem cells. This article also reviews clinical trials employing nonviral gene therapy and discusses the limitations of current technologies. Finally, this article proposes a future strategy to efficiently develop delivery vehicles that might be feasible for clinically relevant nonviral gene therapy, such as high-throughput screening of combinatorial libraries of biomaterials.Display Omitted
Keywords: Nonviral delivery; Genetic medicines; Ischemia; Therapeutic angiogenesis; High-throughput screening
Nonviral delivery of genetic medicine for therapeutic angiogenesis
by Hyun-Ji Park; Fan Yang; Seung-Woo Cho (pp. 40-52).
Genetic medicines that induce angiogenesis represent a promising strategy for the treatment of ischemic diseases. Many types of nonviral delivery systems have been tested as therapeutic angiogenesis agents. However, their delivery efficiency, and consequently therapeutic efficacy, remains to be further improved, as few of these technologies are being used in clinical applications. This article reviews the diverse nonviral gene delivery approaches that have been applied to the field of therapeutic angiogenesis, including plasmids, cationic polymers/lipids, scaffolds, and stem cells. This article also reviews clinical trials employing nonviral gene therapy and discusses the limitations of current technologies. Finally, this article proposes a future strategy to efficiently develop delivery vehicles that might be feasible for clinically relevant nonviral gene therapy, such as high-throughput screening of combinatorial libraries of biomaterials.Display Omitted
Keywords: Nonviral delivery; Genetic medicines; Ischemia; Therapeutic angiogenesis; High-throughput screening
How to improve exposure of tumor cells to drugs — Promoter drugs increase tumor uptake and penetration of effector drugs
by Fabrizio Marcucci; Angelo Corti (pp. 53-68).
Solid tumors are characterized by an abnormal architecture and composition that limit the uptake and distribution of antitumor drugs. Over the last two decades, drugs have been identified that improve the tumor uptake and distribution of drugs that have direct antitumor effects. We propose to refer to these drugs as promoter drugs, and as effector drugs to drugs that have direct antitumor effects. Some promoter drugs have received regulatory approval, while others are in active clinical development. This review gives an overview of promoter drugs, by classifying them according to their mechanism of action: promoter drugs that modulate tumor blood flow, modify the barrier function of tumor vessels, induce tumor cell killing, and overcome stromal barriers. Eventually, we discuss those that we feel are the main conclusions to be drawn from promoter drug research that has been performed so far, and suggest areas of future investigation to improve the efficacy of promoter drugs in cancer therapy.Display Omitted
Keywords: Abbreviations; 5-FU; 5-fluoruracil; ECM; extracellular matrix; EGFR; epidermal growth factor receptor; EPR; enhanced permeability and retention; HER2; human epidermal growth factor-2; IFP; interstitial fluid pressure; IL; interleukin; iRGD; internalizing RGD; i.v.; intravenous; PEP; vasopermeability-enhancing peptide; PDGF; platelet-derived growth factor; PG; prostaglandin; scFv; single-chain fragment variable; TGF; transforming growth factor; TNF; tumor necrosis factor α; VE-cadherin; vascular endothelial-cadherin; VEGF; vascular endothelial growth factor; VEGFR2; VEGF receptor-2 (VEGFR2)Tumor architecture and composition; Tumor uptake and distribution of drugs; Tumor blood flow; Barrier function of tumor vessels; Tumor cell killing; Stromal barriers; Promoter drug research and development; Future investigations in promoter drug research
How to improve exposure of tumor cells to drugs — Promoter drugs increase tumor uptake and penetration of effector drugs
by Fabrizio Marcucci; Angelo Corti (pp. 53-68).
Solid tumors are characterized by an abnormal architecture and composition that limit the uptake and distribution of antitumor drugs. Over the last two decades, drugs have been identified that improve the tumor uptake and distribution of drugs that have direct antitumor effects. We propose to refer to these drugs as promoter drugs, and as effector drugs to drugs that have direct antitumor effects. Some promoter drugs have received regulatory approval, while others are in active clinical development. This review gives an overview of promoter drugs, by classifying them according to their mechanism of action: promoter drugs that modulate tumor blood flow, modify the barrier function of tumor vessels, induce tumor cell killing, and overcome stromal barriers. Eventually, we discuss those that we feel are the main conclusions to be drawn from promoter drug research that has been performed so far, and suggest areas of future investigation to improve the efficacy of promoter drugs in cancer therapy.Display Omitted
Keywords: Abbreviations; 5-FU; 5-fluoruracil; ECM; extracellular matrix; EGFR; epidermal growth factor receptor; EPR; enhanced permeability and retention; HER2; human epidermal growth factor-2; IFP; interstitial fluid pressure; IL; interleukin; iRGD; internalizing RGD; i.v.; intravenous; PEP; vasopermeability-enhancing peptide; PDGF; platelet-derived growth factor; PG; prostaglandin; scFv; single-chain fragment variable; TGF; transforming growth factor; TNF; tumor necrosis factor α; VE-cadherin; vascular endothelial-cadherin; VEGF; vascular endothelial growth factor; VEGFR2; VEGF receptor-2 (VEGFR2)Tumor architecture and composition; Tumor uptake and distribution of drugs; Tumor blood flow; Barrier function of tumor vessels; Tumor cell killing; Stromal barriers; Promoter drug research and development; Future investigations in promoter drug research
Lessons from innovation in drug-device combination products
by Daniela S. Couto; Luis Perez-Breva; Pedro Saraiva; Charles L. Cooney (pp. 69-77).
Drug-device combination products introduced a new dynamic on medical product development, regulatory approval, and corporate interaction that provide valuable lessons for the development of new generations of combination products. This paper examines the case studies of drug-eluting stents and transdermal patches to facilitate a detailed understanding of the challenges and opportunities introduced by combination products when compared to previous generations of traditional medical or drug delivery devices. Our analysis indicates that the largest barrier to introduce a new kind of combination products is the determination of the regulatory center that is to oversee its approval. The first product of a new class of combination products offers a learning opportunity for the regulator and the sponsor. Once that first product is approved, the leading regulatory center is determined, and the uncertainty about the entire class of combination products is drastically reduced. The sponsor pioneering a new class of combination products assumes a central role in reducing this uncertainty by advising the decision on the primary function of the combination product. Our analysis also suggests that this decision influences the nature (pharmaceutical, biotechnology, or medical devices) of the companies that will lead the introduction of these products into the market, and guide the structure of corporate interaction thereon.Display Omitted
Keywords: controlled drug delivery; transdermal patches; drug-eluting stents; primary mode of action
Lessons from innovation in drug-device combination products
by Daniela S. Couto; Luis Perez-Breva; Pedro Saraiva; Charles L. Cooney (pp. 69-77).
Drug-device combination products introduced a new dynamic on medical product development, regulatory approval, and corporate interaction that provide valuable lessons for the development of new generations of combination products. This paper examines the case studies of drug-eluting stents and transdermal patches to facilitate a detailed understanding of the challenges and opportunities introduced by combination products when compared to previous generations of traditional medical or drug delivery devices. Our analysis indicates that the largest barrier to introduce a new kind of combination products is the determination of the regulatory center that is to oversee its approval. The first product of a new class of combination products offers a learning opportunity for the regulator and the sponsor. Once that first product is approved, the leading regulatory center is determined, and the uncertainty about the entire class of combination products is drastically reduced. The sponsor pioneering a new class of combination products assumes a central role in reducing this uncertainty by advising the decision on the primary function of the combination product. Our analysis also suggests that this decision influences the nature (pharmaceutical, biotechnology, or medical devices) of the companies that will lead the introduction of these products into the market, and guide the structure of corporate interaction thereon.Display Omitted
Keywords: controlled drug delivery; transdermal patches; drug-eluting stents; primary mode of action
Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis
by Nathalie Symens; Stefaan J. Soenen; Joanna Rejman; Kevin Braeckmans; Stefaan C. De Smedt; Katrien Remaut (pp. 78-94).
The nucleocytoplasmic partitioning of nanoparticles as a result of cell division is highly relevant to the field of nonviral gene delivery. We reviewed the literature on the intracellular distribution of cell organelles (the endosomal vesicles, Golgi apparatus, endoplasmic reticulum and nucleus), foreign macromolecules (dextrans and plasmid DNA) and inorganic nanoparticles (gold, quantum dot and iron oxide) during mitosis. For nonviral gene delivery particles (lipid- or polymer-based), indirect proof of nuclear entry during mitosis is provided. We also describe how retroviruses and latent DNA viruses take advantage of mitosis to transfer their viral genome and segregate their episomes into the host daughter nuclei. Based on this knowledge, we propose strategies to improve nonviral gene delivery in dividing cells with the ultimate goal of designing nonviral gene delivery systems that are as efficient as their viral counterparts but non-immunogenic, non-oncogenic and easy and inexpensive to prepare.Display Omitted
Keywords: Abbreviations; ASV; avian sarcoma virus; AT; adenosine monophosphate thymidine monophosphate; BPV; bovine papillomavirus; Brd4; double bromodomain protein 4; CDK; cyclin-dependent kinase; EBNA1; Epstein Barr virus nuclear antigen 1; EBV; Epstein Barr virus; ER; endoplasmic reticulum; FV; foamy virus; H2A-H2B; histone 2A-histone 2B pocket; HHV; human herpesvirus; HIV; human immunodeficiency virus; HPV; human papillomavirus; HVS; herpesvirus saimiri; INM; inner nuclear membrane; IONP; iron oxide nanoparticles; KSHV; Kaposi sarcoma associated herpesvirus; LANA; latency associated nuclear antigen; LEDGF/p75; endogenous lens epithelium derived growth factor/p75; LEM; Lap2, Emerin, Man1; MuLV; murine leukemia virus; NE; nuclear envelope; NEBD; nuclear envelope breakdown; NLS; nuclear localization signal; NPC; nuclear pore complex; ONM; outer nuclear membrane; PEI; polyethyleneimine; PIC; pre-integration complex; QD; quantum dot; SNV; spleen necrosis virus; SV40; Simian vacuolating virus 40; XNER; Xenopus; nuclear envelope reassemblyNonviral gene therapy or delivery particles; Quantum dots; Gold particles; Retroviruses; Latent viruses; Dextran; Plasmid DNA; Cell division; Cell cycle; Nucleus
Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis
by Nathalie Symens; Stefaan J. Soenen; Joanna Rejman; Kevin Braeckmans; Stefaan C. De Smedt; Katrien Remaut (pp. 78-94).
The nucleocytoplasmic partitioning of nanoparticles as a result of cell division is highly relevant to the field of nonviral gene delivery. We reviewed the literature on the intracellular distribution of cell organelles (the endosomal vesicles, Golgi apparatus, endoplasmic reticulum and nucleus), foreign macromolecules (dextrans and plasmid DNA) and inorganic nanoparticles (gold, quantum dot and iron oxide) during mitosis. For nonviral gene delivery particles (lipid- or polymer-based), indirect proof of nuclear entry during mitosis is provided. We also describe how retroviruses and latent DNA viruses take advantage of mitosis to transfer their viral genome and segregate their episomes into the host daughter nuclei. Based on this knowledge, we propose strategies to improve nonviral gene delivery in dividing cells with the ultimate goal of designing nonviral gene delivery systems that are as efficient as their viral counterparts but non-immunogenic, non-oncogenic and easy and inexpensive to prepare.Display Omitted
Keywords: Abbreviations; ASV; avian sarcoma virus; AT; adenosine monophosphate thymidine monophosphate; BPV; bovine papillomavirus; Brd4; double bromodomain protein 4; CDK; cyclin-dependent kinase; EBNA1; Epstein Barr virus nuclear antigen 1; EBV; Epstein Barr virus; ER; endoplasmic reticulum; FV; foamy virus; H2A-H2B; histone 2A-histone 2B pocket; HHV; human herpesvirus; HIV; human immunodeficiency virus; HPV; human papillomavirus; HVS; herpesvirus saimiri; INM; inner nuclear membrane; IONP; iron oxide nanoparticles; KSHV; Kaposi sarcoma associated herpesvirus; LANA; latency associated nuclear antigen; LEDGF/p75; endogenous lens epithelium derived growth factor/p75; LEM; Lap2, Emerin, Man1; MuLV; murine leukemia virus; NE; nuclear envelope; NEBD; nuclear envelope breakdown; NLS; nuclear localization signal; NPC; nuclear pore complex; ONM; outer nuclear membrane; PEI; polyethyleneimine; PIC; pre-integration complex; QD; quantum dot; SNV; spleen necrosis virus; SV40; Simian vacuolating virus 40; XNER; Xenopus; nuclear envelope reassemblyNonviral gene therapy or delivery particles; Quantum dots; Gold particles; Retroviruses; Latent viruses; Dextran; Plasmid DNA; Cell division; Cell cycle; Nucleus
Improving the prediction of the brain disposition for orally administered drugs using BDDCS
by Fabio Broccatelli; Caroline A. Larregieu; Gabriele Cruciani; Tudor I. Oprea; Leslie Z. Benet (pp. 95-109).
In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.Display Omitted
Keywords: Abbreviations; BDDCS; Biopharmaceutics drug disposition classification system; BBB; Blood–brain barrier; Pgp; P-glycoprotein; CNS; Central nervous systemBrain disposition; Data mining; Drug discovery; Rules of thumb
Improving the prediction of the brain disposition for orally administered drugs using BDDCS
by Fabio Broccatelli; Caroline A. Larregieu; Gabriele Cruciani; Tudor I. Oprea; Leslie Z. Benet (pp. 95-109).
In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.Display Omitted
Keywords: Abbreviations; BDDCS; Biopharmaceutics drug disposition classification system; BBB; Blood–brain barrier; Pgp; P-glycoprotein; CNS; Central nervous systemBrain disposition; Data mining; Drug discovery; Rules of thumb
Role of engineered nanocarriers for axon regeneration and guidance: Current status and future trends
by Somesree GhoshMitra; David R. Diercks; Nathaniel C. Mills; DiAnna L. Hynds; Santaneel Ghosh (pp. 110-125).
There are approximately 1.5million people who experience traumatic injuries to the brain and 265,000 who experience traumatic injuries to the spinal cord each year in the United States. Currently, there are few effective treatments for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. Smart, remotely tunable, multifunctional micro- and nanocarriers hold promise for delivering treatments to the CNS and targeting specific neurons to enhance axon regeneration and synaptogenesis. Furthermore, assessing the efficacy of treatments could be enhanced by biocompatible nanovectors designed for imaging in vivo. Recent developments in nanoengineering offer promising alternatives for designing biocompatible micro- and nanovectors, including magnetic nanostructures, carbon nanotubes, and quantum dot-based systems for controlled release of therapeutic and diagnostic agents to targeted CNS cells. This review highlights recent achievements in the development of smart nanostructures to overcome the existing challenges for treating CNS injuries.Display Omitted
Keywords: Central nervous system injury; Axon regeneration and guidance; Engineered nanocarriers; Micro- and nano fabricated neural devices; Remote controlled release; Neurotoxicity
Role of engineered nanocarriers for axon regeneration and guidance: Current status and future trends
by Somesree GhoshMitra; David R. Diercks; Nathaniel C. Mills; DiAnna L. Hynds; Santaneel Ghosh (pp. 110-125).
There are approximately 1.5million people who experience traumatic injuries to the brain and 265,000 who experience traumatic injuries to the spinal cord each year in the United States. Currently, there are few effective treatments for central nervous system (CNS) injuries because the CNS is refractory to axonal regeneration and relatively inaccessible to many pharmacological treatments. Smart, remotely tunable, multifunctional micro- and nanocarriers hold promise for delivering treatments to the CNS and targeting specific neurons to enhance axon regeneration and synaptogenesis. Furthermore, assessing the efficacy of treatments could be enhanced by biocompatible nanovectors designed for imaging in vivo. Recent developments in nanoengineering offer promising alternatives for designing biocompatible micro- and nanovectors, including magnetic nanostructures, carbon nanotubes, and quantum dot-based systems for controlled release of therapeutic and diagnostic agents to targeted CNS cells. This review highlights recent achievements in the development of smart nanostructures to overcome the existing challenges for treating CNS injuries.Display Omitted
Keywords: Central nervous system injury; Axon regeneration and guidance; Engineered nanocarriers; Micro- and nano fabricated neural devices; Remote controlled release; Neurotoxicity
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