Dendrimer-Based Drug Delivery Systems for Brain Targeting

Human neuroscience has made remarkable progress in understanding basic aspects of functional organization; it is a renowned fact that the blood–brain barrier (BBB) impedes the permeation and access of most drugs to central nervous system (CNS) and that many neurological diseases remain undertreated. Therefore, a number of nanocarriers have been designed over the past few decades to deliver drugs to the brain. Among these nanomaterials, dendrimers have procured an enormous attention from scholars because of their nanoscale uniform size, ease of multi-functionalization, and available internal cavities. As hyper-branched 3D macromolecules, dendrimers can be maneuvered to transport diverse therapeutic agents, incorporating small molecules, peptides, and genes; diminishing their cytotoxicity; and improving their efficacy. Herein, the present review will give exhaustive details of extensive researches in the field of dendrimer-based vehicles to deliver drugs through the BBB in a secure and effectual manner. It is also a souvenir in commemorating Donald A. Tomalia on his 80th birthday.

[1]  J. Cladera,et al.  Effect of poly(propylene imine) glycodendrimers on β-amyloid aggregation in vitro and in APP/PS1 transgenic mice, as a model of brain amyloid deposition and Alzheimer's disease. , 2013, Biomacromolecules.

[2]  J. Sheng,et al.  Co-delivery of as-miR-21 and 5-FU by Poly(amidoamine) Dendrimer Attenuates Human Glioma Cell Growth in Vitro , 2010, Journal of biomaterials science. Polymer edition.

[3]  Chen Jiang,et al.  Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. , 2009, Biomaterials.

[4]  J. Rossignol,et al.  Use of Polyamidoamine Dendrimers in Brain Diseases , 2018, Molecules.

[5]  Hongzhe Sun,et al.  Targeted Drug Delivery via the Transferrin Receptor-Mediated Endocytosis Pathway , 2002, Pharmacological Reviews.

[6]  I. Bravo-Osuna,et al.  Combination therapy and co-delivery strategies to optimize treatment of posterior segment neurodegenerative diseases. , 2019, Drug discovery today.

[7]  Seungpyo Hong,et al.  Dendrimer-based nanocarriers: a versatile platform for drug delivery. , 2017, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[8]  V. Chekhonin,et al.  VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[9]  Liang Feng,et al.  The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood-brain barrier after modification with lactoferrin. , 2014, Nanoscale.

[10]  B. Davidson,et al.  Transvascular delivery of small interfering RNA to the central nervous system , 2007, Nature.

[11]  Rajendran J C Bose,et al.  Intranasal delivery of targeted polyfunctional gold-iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide. , 2019, Biomaterials.

[12]  Morgan Le Guen,et al.  Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids. , 2012, Pharmacology & therapeutics.

[13]  M. Brechbiel,et al.  Micro‐MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: Reference to pharmacokinetic properties of dendrimer‐based MR contrast agents , 2001, Journal of magnetic resonance imaging : JMRI.

[14]  B. Zhang,et al.  Biomimetic nanoparticles for inflammation targeting , 2017, Acta pharmaceutica Sinica. B.

[15]  Xin Du,et al.  Developing Functionalized Dendrimer‐Like Silica Nanoparticles with Hierarchical Pores as Advanced Delivery Nanocarriers , 2013, Advanced materials.

[16]  M. Johnston,et al.  Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[17]  R. Liu,et al.  Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy. , 2018, Biomaterials.

[18]  Shweta Gupta,et al.  Approaches for CNS delivery of drugs – nose to brain targeting of antiretroviral agents as a potential attempt for complete elimination of major reservoir site of HIV to aid AIDS treatment , 2019, Expert opinion on drug delivery.

[19]  Anders Hult,et al.  Stability and biocompatibility of a library of polyester dendrimers in comparison to polyamidoamine dendrimers. , 2012, Biomaterials.

[20]  Rongqin Huang,et al.  Efficient gene delivery targeted to the brain using a transferrin-conjugated polyethyleneglycol-modified polyamidoamine dendrimer , 2007 .

[21]  M. Gomori,et al.  In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. , 2000, Journal of neurosurgery.

[22]  Kaili Hu,et al.  Chitosan and chitosan coating nanoparticles for the treatment of brain disease , 2019, International journal of pharmaceutics.

[23]  A. Caminade,et al.  Nanomaterials based on phosphorus dendrimers. , 2004, Accounts of chemical research.

[24]  Tong-ying Jiang,et al.  Trimethylated chitosan-conjugated PLGA nanoparticles for the delivery of drugs to the brain. , 2010, Biomaterials.

[25]  Rongqin Huang,et al.  Choline‐Derivate‐Modified Nanoparticles for Brain‐Targeting Gene Delivery , 2011, Advanced materials.

[26]  Aruna Sharma,et al.  Influence of engineered nanoparticles from metals on the blood-brain barrier permeability, cerebral blood flow, brain edema and neurotoxicity. An experimental study in the rat and mice using biochemical and morphological approaches. , 2009, Journal of nanoscience and nanotechnology.

[27]  A. Olivi,et al.  New Approach to Tumor Therapy for Inoperable Areas of the Brain: Chronic Intraparenchymal Drug Delivery , 2002, Journal of Neuro-Oncology.

[28]  S. Bhatia,et al.  Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries. , 2016, ACS nano.

[29]  W. Frey,et al.  Intranasal delivery to the central nervous system: mechanisms and experimental considerations. , 2010, Journal of pharmaceutical sciences.

[30]  Philip E. Dawson,et al.  Delivery and tracking of quantum dot peptide bioconjugates in an intact developing avian brain. , 2015, ACS chemical neuroscience.

[31]  K. Lee,et al.  Effects of dopamine concentration on energy transfer between dendrimer-QD and dye-labeled antibody. , 2009, Ultramicroscopy.

[32]  T. Mocan,et al.  Quantum dots in imaging, drug delivery and sensor applications , 2017, International journal of nanomedicine.

[33]  Positively charged phosphorus dendrimers. An overview of their properties , 2013 .

[34]  Viney Lather,et al.  Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues , 2014, Journal of pharmacy & bioallied sciences.

[35]  John A. Kessler,et al.  Nanotechnology—novel therapeutics for CNS disorders , 2012, Nature Reviews Neurology.

[36]  A. Venyaminova,et al.  Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (A). Mechanisms of interaction. , 2015, International journal of pharmaceutics.

[37]  D. Tomalia,et al.  Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. , 2001, Drug discovery today.

[38]  Linyin Feng,et al.  Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model , 2010, Journal of the Neurological Sciences.

[39]  Jong-sang Park,et al.  Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust neuroprotection in the postischemic brain. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[40]  V. Mishra,et al.  Dendrimer-mediated approaches for the treatment of brain tumor , 2016, Journal of biomaterials science. Polymer edition.

[41]  Xuesi Chen,et al.  A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[42]  Chen Jiang,et al.  The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. , 2008, Biomaterials.

[43]  F. Caruso,et al.  Overcoming the Blood–Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases , 2018, Advanced materials.

[44]  Sanjiv S Gambhir,et al.  Nanooncology: The future of cancer diagnosis and therapy , 2013, CA: a cancer journal for clinicians.

[45]  S. Álvarez,et al.  In vivo delivery of siRNA to the brain by carbosilane dendrimer. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[46]  Huile Gao,et al.  Integrin-mediated active tumor targeting and tumor microenvironment response dendrimer-gelatin nanoparticles for drug delivery and tumor treatment. , 2015, International journal of pharmaceutics.

[47]  V. Aswal,et al.  Effect of the Branching Pattern of Hydrophobic Dendrons on the Core Structure of Linear‐Dendritic Copolymer Micelles , 2014 .

[48]  R. Deane,et al.  RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid &bgr;-Peptide Clearance Through Transport Across the Blood–Brain Barrier , 2004, Stroke.

[49]  Yoshinobu Manome,et al.  Cell-Based in Vitro Blood–Brain Barrier Model Can Rapidly Evaluate Nanoparticles’ Brain Permeability in Association with Particle Size and Surface Modification , 2014, International journal of molecular sciences.

[50]  T. Weil,et al.  Cationic PAMAM Dendrimers as Pore-Blocking Binary Toxin Inhibitors , 2014, Biomacromolecules.

[51]  Yan Li,et al.  A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas. , 2012, Biomaterials.

[52]  N. Patel,et al.  GDNF, NGF and BDNF as therapeutic options for neurodegeneration. , 2013, Pharmacology & therapeutics.

[53]  O. Ogawa,et al.  Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. , 2002, International journal of oncology.

[54]  Guanmin Meng,et al.  Strategies for transporting nanoparticles across the blood-brain barrier. , 2016, Biomaterials science.

[55]  Chungkyun Kim,et al.  Carbosilane and Carbosiloxane Dendrimers , 2009, Molecules.

[56]  M. Kinch An analysis of FDA-approved drugs for neurological disorders. , 2015, Drug discovery today.

[57]  Rongqin Huang,et al.  Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[58]  Xin-guo Jiang,et al.  Perspectives on brain-targeting drug delivery systems. , 2012, Current pharmaceutical biotechnology.

[59]  Xinguo Jiang,et al.  Combination of TRAIL and actinomycin D liposomes enhances antitumor effect in non-small cell lung cancer , 2012, International journal of nanomedicine.

[60]  Chen Jiang,et al.  Gene and doxorubicin co-delivery system for targeting therapy of glioma. , 2012, Biomaterials.

[61]  武田 真莉子 バイオ医薬のNose-to-Brain Delivery戦略 , 2016 .

[62]  R. Duncan,et al.  Dendrimer biocompatibility and toxicity. , 2005, Advanced drug delivery reviews.

[63]  J. Roovers,et al.  Synthesis of novel carbosilane dendritic macromolecules , 1993 .

[64]  Lu Wen,et al.  Novel multiple agents loaded PLGA nanoparticles for brain delivery via inner ear administration: in vitro and in vivo evaluation. , 2013, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[65]  J. Herz,et al.  Coaxing the LDL Receptor Family into the Fold , 2003, Cell.

[66]  Y. Katare,et al.  Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer. , 2015, Molecular pharmaceutics.

[67]  F. Szoka,et al.  Chloride Accumulation and Swelling in Endosomes Enhances DNA Transfer by Polyamine-DNA Polyplexes* , 2003, Journal of Biological Chemistry.

[68]  N. K. Jain,et al.  Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment. , 2016, Journal of colloid and interface science.

[69]  N. K. Jain,et al.  Toxicity of nanostructured biomaterials , 2018 .

[70]  Chen Jiang,et al.  Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer. , 2011, Biomaterials.

[71]  R. Kannan,et al.  Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation. , 2018, International journal of pharmaceutics.

[72]  Chen Jiang,et al.  T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting. , 2013, International journal of pharmaceutics.

[73]  Steve P. Rannard,et al.  Dendrimers: a new class of nanoscopic containers and delivery devices , 2003 .

[74]  M. Farah,et al.  Progress and challenges in probing the human brain , 2015, Nature.

[75]  Xuesi Chen,et al.  Polylysine-modified polyethylenimine (PEI-PLL) mediated VEGF gene delivery protects dopaminergic neurons in cell culture and in rat models of Parkinson's Disease (PD). , 2017, Acta biomaterialia.

[76]  Anjali Sharma,et al.  Effect of mannose targeting of hydroxyl PAMAM dendrimers on cellular and organ biodistribution in a neonatal brain injury model , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[77]  W. Xu,et al.  Linear-dendritic block copolymer for drug and gene delivery. , 2016, Materials science & engineering. C, Materials for biological applications.

[78]  A. Falcão,et al.  Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges. , 2019, Drug discovery today.

[79]  Hui Xiong,et al.  LMWH and its derivatives represent new rational for cancer therapy: construction strategies and combination therapy. , 2019, Drug discovery today.

[80]  Rongrong Hua,et al.  Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats. , 2010, Molecular pharmaceutics.

[81]  J. Kim,et al.  Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas , 2011, Oncogene.

[82]  Maria Jose Morilla,et al.  Selective cytotoxicity of PAMAM G5 core–PAMAM G2.5 shell tecto-dendrimers on melanoma cells , 2012, International journal of nanomedicine.

[83]  J. Cladera,et al.  Dense shell glycodendrimers as potential nontoxic anti-amyloidogenic agents in Alzheimer's disease. Amyloid-dendrimer aggregates morphology and cell toxicity. , 2011, Biomacromolecules.

[84]  Jian Qin,et al.  The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications. , 2006, Nano letters.

[85]  I. Mills Across the divide , 1985, Nature.

[86]  F. Gorin,et al.  Perinecrotic glioma proliferation and metabolic profile within an intracerebral tumor xenograft , 2004, Acta Neuropathologica.

[87]  R. Jain,et al.  Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[88]  W. Banks,et al.  Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. , 2014, Pharmacology & therapeutics.

[89]  Piyush Gondaliya,et al.  ‘Dendrimer‐Cationized‐Albumin’ encrusted polymeric nanoparticle improves BBB penetration and anticancer activity of doxorubicin , 2019, International journal of pharmaceutics.

[90]  A. Caminade,et al.  Phosphorus dendrimers affect Alzheimer's (Aβ1-28) peptide and MAP-Tau protein aggregation. , 2012, Molecular pharmaceutics.

[91]  W. Geldenhuys,et al.  The blood-brain barrier choline transporter. , 2012, Central nervous system agents in medicinal chemistry.

[92]  A. Sherje,et al.  Dendrimers: A versatile nanocarrier for drug delivery and targeting , 2018, International journal of pharmaceutics.

[93]  Christine Dufès,et al.  Applications of dendrimers for brain delivery and cancer therapy. , 2014, Nanomedicine.

[94]  M. Pistello,et al.  Viral vectors: a look back and ahead on gene transfer technology. , 2013, The new microbiologica.

[95]  T. Takeuchi,et al.  Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves. , 2003, The Journal of veterinary medical science.

[96]  K. Hynynen,et al.  Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology. , 2012, Neurosurgical focus.

[97]  D. Begley,et al.  Structural and functional aspects of the blood-brain barrier. , 2003, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[98]  Seungpyo Hong,et al.  The role of ganglioside GM1 in cellular internalization mechanisms of poly(amidoamine) dendrimers. , 2009, Bioconjugate chemistry.

[99]  T. W. Secomb,et al.  The endothelial surface layer , 2000, Pflügers Archiv.

[100]  S. Ju,et al.  Multimodal Nanoprobes Evaluating Physiological Pore Size of Brain Vasculatures in Ischemic Stroke Models , 2014, Advanced healthcare materials.

[101]  Xin-guo Jiang,et al.  Enhanced intracellular delivery and chemotherapy for glioma rats by transferrin-conjugated biodegradable polymersomes loaded with doxorubicin. , 2011, Bioconjugate chemistry.

[102]  F. Cupaioli,et al.  Engineered nanoparticles. How brain friendly is this new guest? , 2014, Progress in Neurobiology.

[103]  V. Mishra,et al.  Dendrimer technologies for brain tumor. , 2016, Drug discovery today.

[104]  M. Johnston,et al.  Uptake of dendrimer-drug by different cell types in the hippocampus after hypoxic-ischemic insult in neonatal mice: Effects of injury, microglial activation and hypothermia. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[105]  A. Nairn Faculty of 1000 evaluation for GDNF, NGF and BDNF as therapeutic options for neurodegeneration. , 2016 .

[106]  Quanyin Hu,et al.  Sequentially Site-Specific Delivery of Thrombolytics and Neuroprotectant for Enhanced Treatment of Ischemic Stroke. , 2019, ACS nano.

[107]  N. K. Jain,et al.  Investigations on biodistribution of technetium-99m-labeled carbohydrate-coated poly(propylene imine) dendrimers. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[108]  J. Hatton,et al.  Intracerebroventricular Administration of Drugs , 2009, Pharmacotherapy.

[109]  Yongzhuo Huang,et al.  Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides , 2016, Acta pharmaceutica Sinica. B.

[110]  Rongqin Huang,et al.  Neuroprotection in a 6‐hydroxydopamine‐lesioned Parkinson model using lactoferrin‐modified nanoparticles , 2009, The journal of gene medicine.

[111]  T. Deer,et al.  Intrathecal drug delivery for pain management: recent advances and future developments , 2019, Expert opinion on drug delivery.

[112]  C. Surber,et al.  Nasal drug delivery in humans. , 2011, Current problems in dermatology.

[113]  H. Luhmann,et al.  Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates , 2018, Advanced science.

[114]  S. Cryan,et al.  Molecular weight and architectural dependence of well-defined star-shaped poly(lysine) as a gene delivery vector. , 2013, Biomaterials science.

[115]  Decheng Wu,et al.  Biodegradable dendrimers for drug delivery. , 2018, Materials science & engineering. C, Materials for biological applications.

[116]  Chen Jiang,et al.  Brain-targeting gene delivery and cellular internalization mechanisms for modified rabies virus glycoprotein RVG29 nanoparticles. , 2009, Biomaterials.

[117]  Prashant Kesharwani,et al.  Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. , 2015, Drug discovery today.

[118]  D. Manzanares,et al.  Evaluation of Amino-Functional Polyester Dendrimers Based on Bis-MPA as Nonviral Vectors for siRNA Delivery , 2018, Molecules.

[119]  Labchan Rajbhandari,et al.  Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture , 2018, Molecules.

[120]  T. Tsumuraya,et al.  General strategy for the systematic synthesis of oligosiloxanes. Silicone dendrimers , 1990 .

[121]  M. Malý,et al.  Influence of surface groups on poly(propylene imine) dendrimers antiprion activity. , 2013, Biomacromolecules.

[122]  Chen Jiang,et al.  Choline transporter-targeting and co-delivery system for glioma therapy. , 2013, Biomaterials.

[123]  H. Ghandehari,et al.  Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. , 2012, Advanced drug delivery reviews.

[124]  J. Feijen,et al.  Dual-targeted nanomedicines for enhanced tumor treatment , 2018 .

[125]  M. Aghi,et al.  Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. , 2017, Journal of neurosurgery.

[126]  Keerti Jain,et al.  Dendrimer nanohybrid carrier systems: an expanding horizon for targeted drug and gene delivery. , 2017, Drug discovery today.

[127]  Huile Gao,et al.  Progress and perspectives on targeting nanoparticles for brain drug delivery , 2016, Acta pharmaceutica Sinica. B.

[128]  S. Tucker,et al.  Spectroscopic investigations of poly(propyleneimine)dendrimers using the solvatochromic probe phenol blue and comparisons to poly(amidoamine) dendrimers. , 2001, Analytical chemistry.

[129]  Fanzhu Li,et al.  A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration. , 2016, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[130]  A. Caminade,et al.  Validation of a generation 4 phosphorus-containing polycationic dendrimer for gene delivery against HIV-1. , 2012, Current medicinal chemistry.

[131]  E. W. Meijer,et al.  Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[132]  B. Baradaran,et al.  Surface functionalized dendrimers as controlled‐release delivery nanosystems for tumor targeting , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[133]  Xinguo Jiang,et al.  Co-delivery of pEGFP-hTRAIL and paclitaxel to brain glioma mediated by an angiopep-conjugated liposome. , 2011, Biomaterials.

[134]  Raghu Raghavan,et al.  Convection-enhanced delivery of therapeutics for brain disease, and its optimization. , 2006, Neurosurgical focus.

[135]  Sami Nummelin,et al.  High-Generation Amphiphilic Janus-Dendrimers as Stabilizing Agents for Drug Suspensions. , 2018, Biomacromolecules.

[136]  Wentao Dai,et al.  Route to Rheumatoid Arthritis by Macrophage-Derived Microvesicle-Coated Nanoparticles. , 2018, Nano letters.

[137]  J. Scherrmann,et al.  CNS Delivery Via Adsorptive Transcytosis , 2008, The AAPS Journal.

[138]  G. Salzano,et al.  Nanotech revolution for the anti-cancer drug delivery through blood-brain barrier. , 2012, Current cancer drug targets.

[139]  R. Gilbert,et al.  Challenges of gene delivery to the central nervous system and the growing use of biomaterial vectors , 2019, Brain Research Bulletin.

[140]  P F Morrison,et al.  Convection-enhanced delivery of macromolecules in the brain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[141]  K. Rissanen,et al.  Synthesis and thermal behavior of Janus dendrimers, part 2 , 2010 .

[142]  D. Stepensky,et al.  Quantitative analysis of drug delivery to the brain via nasal route. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[143]  Ashwini Patel,et al.  Intranasal drug delivery: Novel delivery route for effective management of neurological disorders , 2019, Journal of Drug Delivery Science and Technology.

[144]  W. Mark Saltzman,et al.  Nanotechnology for delivery of drugs to the brain for epilepsy , 2009, Neurotherapeutics.

[145]  Antony D'Emanuele,et al.  Dendrimer-drug interactions. , 2005, Advanced drug delivery reviews.

[146]  “Janus” dendrimers: syntheses and properties , 2012 .

[147]  Xinguo Jiang,et al.  Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles. , 2006, International journal of pharmaceutics.

[148]  E. Pędziwiatr-Werbicka,et al.  Dendrimers and hyperbranched structures for biomedical applications , 2019, European Polymer Journal.

[149]  Rongqin Huang,et al.  Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma. , 2011, Biomaterials.

[150]  Michel Demeule,et al.  High transcytosis of melanotransferrin (P97) across the blood–brain barrier , 2002, Journal of neurochemistry.

[151]  W. Banks,et al.  From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery , 2016, Nature Reviews Drug Discovery.

[152]  Alexander V Kabanov,et al.  Agile delivery of protein therapeutics to CNS. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[153]  Wojciech G. Lesniak,et al.  Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest , 2014, ACS nano.

[154]  A. Beezer,et al.  Dendrimers as potential drug carriers; encapsulation of acidic hydrophobes within water soluble PAMAM derivatives , 2003 .

[155]  S. Hahn,et al.  Nose-to-brain delivery of hyaluronate - FG loop peptide conjugate for Non-invasive hypoxic-ischemic encephalopathy therapy. , 2019, Journal of controlled release : official journal of the Controlled Release Society.

[156]  H. Moghimi,et al.  Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain. , 2015, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[157]  N. K. Jain,et al.  The treatment of Glioblastoma Xenografts by surfactant conjugated dendritic nanoconjugates. , 2011, Biomaterials.

[158]  P. Hildgen,et al.  On the mechanism and dynamics of uptake and permeation of polyether-copolyester dendrimers across an in vitro blood-brain barrier model. , 2009, Journal of pharmaceutical sciences.

[159]  J. Tam,et al.  Peptide dendrimers: applications and synthesis. , 2002, Journal of biotechnology.

[160]  Huile Gao,et al.  Acid‐Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery , 2018, Advanced Functional Materials.

[161]  P. Kesharwani,et al.  Dendrimer toxicity: Let's meet the challenge. , 2010, International journal of pharmaceutics.

[162]  Christopher J H Porter,et al.  PEGylated polylysine dendrimers increase lymphatic exposure to doxorubicin when compared to PEGylated liposomal and solution formulations of doxorubicin. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[163]  Keerti Jain,et al.  Dendrimer as nanocarrier for drug delivery , 2014 .

[164]  E. Hansson,et al.  Astrocyte–endothelial interactions at the blood–brain barrier , 2006, Nature Reviews Neuroscience.

[165]  Z. Gu,et al.  Functional Dendritic Polymer-Based Nanoscale Vehicles for Imaging-Guided Cancer Therapy , 2016 .

[166]  B. Zhang,et al.  CREKA peptide-conjugated dendrimer nanoparticles for glioblastoma multiforme delivery. , 2015, Journal of colloid and interface science.

[167]  Vladimir P Torchilin,et al.  Multifunctional nanocarriers. , 2006, Advanced drug delivery reviews.

[168]  Colin M. Wilson,et al.  Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors , 2009, Journal of Translational Medicine.

[169]  Rui Liu,et al.  Coadministration of iRGD with Multistage Responsive Nanoparticles Enhanced Tumor Targeting and Penetration Abilities for Breast Cancer Therapy. , 2018, ACS applied materials & interfaces.

[170]  S. Kannan,et al.  The effect of surface functionality on cellular trafficking of dendrimers. , 2008, Biomaterials.

[171]  Peng Cao,et al.  Yupingfeng Pulvis Regulates the Balance of T Cell Subsets in Asthma Mice , 2016, Evidence-based complementary and alternative medicine : eCAM.

[172]  Manfred Westphal,et al.  Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration. , 2017, Pediatric neurology.

[173]  Yu Liu,et al.  Recent advances in brain tumor-targeted nano-drug delivery systems , 2012, Expert opinion on drug delivery.

[174]  S. M. Dizaj,et al.  Applications of nanotechnology in drug delivery to the central nervous system. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[175]  W. Pardridge,et al.  Blood-brain barrier delivery. , 2007, Drug discovery today.

[176]  R. Gómez,et al.  Polyanionic carbosilane dendrimer-conjugated antiviral drugs as efficient microbicides: Recent trends and developments in HIV treatment/therapy. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[177]  A. Caminade,et al.  EPR study of the interactions between dendrimers and peptides involved in Alzheimer's and prion diseases. , 2007, Macromolecular bioscience.

[178]  Yuan Yu,et al.  Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes. , 2011, International journal of pharmaceutics.

[179]  S. Kannan,et al.  Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. , 2016, Biomaterials.

[180]  B. Nordén,et al.  Effects of PEGylation and acetylation of PAMAM dendrimers on DNA binding, cytotoxicity and in vitro transfection efficiency. , 2010, Molecular pharmaceutics.

[181]  H. Christou Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model , 2012 .

[182]  P. Mutlu,et al.  Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine , 2014, Journal of Nanoparticle Research.

[183]  M. Bryszewska,et al.  Dendrimers in biomedical applications. , 2012, Current medicinal chemistry.

[184]  Ashish Ranjan Sharma,et al.  Advances in nanocarriers enabled brain targeted drug delivery across blood brain barrier. , 2019, International journal of pharmaceutics.

[185]  Chen Jiang,et al.  Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease , 2013, Pharmaceutical Research.

[186]  Guixue Wang,et al.  Non-invasive approaches for drug delivery to the brain based on the receptor mediated transport. , 2017, Materials science & engineering. C, Materials for biological applications.

[187]  Y. Pei,et al.  RGD-modified PEG-PAMAM-DOX conjugates: in vitro and in vivo studies for glioma. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[188]  D. Fortin,et al.  Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy , 2008, The AAPS Journal.

[189]  B. Pickard,et al.  Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[190]  M. Caligiuri,et al.  Convection-enhanced delivery of boronated epidermal growth factor for molecular targeting of EGF receptor-positive gliomas. , 2002, Cancer research.

[191]  E. W. Meijer,et al.  New Dendrimer–Peptide Host–Guest Complexes: Towards Dendrimers as Peptide Carriers , 2002, Chembiochem : a European journal of chemical biology.

[192]  Wei Lv,et al.  Bioengineered Boronic Ester Modified Dextran Polymer Nanoparticles as Reactive Oxygen Species Responsive Nanocarrier for Ischemic Stroke Treatment. , 2018, ACS nano.

[193]  Jin Sun,et al.  Large amino acid transporter 1 mediated glutamate modified docetaxel-loaded liposomes for glioma targeting. , 2016, Colloids and surfaces. B, Biointerfaces.

[194]  C. Dufès,et al.  Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[195]  Rongqin Huang,et al.  Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration. , 2011, Biomaterials.

[196]  Chi Zhang,et al.  A Dual Targeting Drug Delivery System for Penetrating Blood-Brain Barrier and Selectively Delivering siRNA to Neurons for Alzheimer's Disease Treatment. , 2018, Current pharmaceutical biotechnology.