Approaches for Drug Delivery to the Brain: Comparison
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Please note this is a comparison between Version 2 by Mona Zou and Version 1 by Nagesh Kolishetti.

Brain cancers and neurodegenerative diseases are on the rise, treatments for central nervous system (CNS) diseases remain limited. Despite the significant advancement in drug development technology with emerging biopharmaceuticals like gene therapy or recombinant protein, the clinical translational rate of such biopharmaceuticals to treat CNS disease is extremely poor. The blood–brain barrier (BBB), which separates the brain from blood and protects the CNS microenvironment to maintain essential neuronal functions, poses the greatest challenge for CNS drug delivery. Many strategies have been developed over the years which include local disruption of BBB via physical and chemical methods, and drug transport across BBB via transcytosis by targeting some endogenous proteins expressed on brain-capillary. Drug delivery to brain is an ever-evolving topic, although there were multiple review articles in literature, an update is warranted due to continued growth and new innovations of research on this topic.

  • blood–brain barrier (BBB)
  • focus ultrasound
  • nanocarrier
  • drug delivery to the brain
  • receptor-mediated transcytosis
  • brain tumor

1. Approaches for Drug Delivery through the Blood–Brain Barrier

Over the past few decades, diverse strategies have emerged to enhance the transportation of drugs through the BBB (Figure 21). These strategies include temporary disruption of BBB via physical or chemical means as well as targeting some endogenous transporter systems over-expressed on BBB.
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Figure 21. Summary of drug delivery strategies to brain.

2. Temporary Disruption of BBB

2.1. Osmotic Blood–Brain Barrier Disruption

In this process (Figure 32), BBB permeation is achieved using a hyperosmotic agent which causes dehydration and shrinkage in BCEC resulting tight-junction dysfunction and transient disruption of BBB. This process of osmotic BBB disruption was first hypothesized by Rapoport et al. in 1972 [24][1] following an improved BBB permeation of a dye Evan’s blue when co-administered with hypertonic arabinose and later supported by Brightman et al. who visualize the opening of tight junction with electron microscopy after intra-carotid infusion of mannitol [25][2]. A variety of substances have been used as osmotic disruptors of the BBB including urea, lactamide, saline but mannitol has been most used for this purpose. Since 1980, intracarotid artery hyperosmotic mannitol (ICAHM) infusions has been used for drug delivery to brain in several pre-clinical and clinical studies [26][3] many of which have produced encouraging results of enhanced survivability with clinical safety. For instance, a clinical study conducted in 17 patients with primary CNS lymphoma receiving cyclophosphamide and mannitol followed by radiotherapy significantly enhances the mean survivability (from 17.8 months to 44.5 months) compared with the control group receiving radiotherapy alone [27][4]. Combination of carboplatin and etoposide delivered in this method exhibits an effective delivery in brain and dramatic responses in inhibiting CNS tumor in patients although unexpected high-frequency hearing loss limits the application of the combined chemotherapy [28][5]. Some studies in animal models have demonstrated variable and inconsistent results in BBB permeability like nonselective opening of BBB, CNS toxicity and neuroinflammatory response become the major limitation of this approach [29,30,31][6][7][8]. The success of this strategy depends on multiple factors, including injection speed, optimum mannitol dose, cerebral hemodynamics, and vascular anatomy. Strategies to overcome the limitation are currently under investigation, e.g., use of real time MRI guidance for optimum and targeted delivery of therapeutics [32,33][9][10]. Overall, mannitol mediated osmotic disruption of BBB for drug delivery to brain is safe and hold promise while further investigation is needed to improve its reproducibility and clinical effectiveness.
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Figure 32. Schematic of focus ultrasound-mediated (A) and osmotic (B) disruption of BBB.

2.2. BBB Disruption with Focused Ultrasound

In this method (Figure 32) local BBB permeation can be achieved by using focused ultrasound (FUS) in combination with intravenous microbubbles and can be monitored by using MR-imaging system. This method has several advantages over other methods. It is reproducible, non-invasive, and targeted opening of the BBB can be achieved. In addition, the BBB opening is transient which can be restored within 6 to 24 h allowing accumulation of therapeutics in the region of interest for a desired time window.
The FUS technology was first introduced in 1950s initially to treat psychiatric disorders and brain tumors although those early attempts were invasive involving craniectomy to introduce sonication into brain which has been evolved to non-invasive over time by decades of research [34,35,36,37][11][12][13][14]. Although the minimal invasiveness to reduce surgical trauma and recovery time are the driving force, the skull bone which varies in thickness and density among individuals greatly attenuates and distorts ultrasound. In addition, hair, which introduces air, significantly (up to 80%) distorts the delivery of ultrasound. The implementation of phased array transducers along with real-time MRI-thermal monitoring has been a breakthrough in this century to made non-invasive transcranial FUS feasible [37][14].
The cellular and molecular mechanism of FUS-mediated enhanced BBB permeation is poorly understood. The sheer stress from the stable acoustic cavitation of the microbubbles induces structural and functional modulation in the BBB like higher caveolae formation, sonoporation, as well as opening of some tight junctions which enhance intracellular and paracellular transport [38,39,40][15][16][17]. Although stable cavitation contributes to loosening of tight junction, inertial cavitation may contribute to hemorrhage and ischemia. Nonetheless, microbubble cavitation can be controlled by tuning ultrasound pressure amplitude and low-frequency FUS-mediated BBB opening rule out the thermal effect on the BBB. Notably, FUS activates PI3kinase/Akt pathway in neuronal cells which may play role in modulation of tight junction proteins ZO-1 and occludin [41][18]. Cerebral vessels are resilient to such mechanical stress caused by stable microbubbles cavitation and quickly recover their integrity after the FUS.
As indicated before, FUS can induce local and targeted opening of the BBB with a desired time window. The extent of BBB opening can be controlled by tuning ultrasound pressure amplitude, transducer frequency, microbubble size and dosage, exposure duration and burst parameters [42,43,44][19][20][21]. For instance, a study by Chen et al. has demonstrated that FUS can enable trans-BBB delivery of dextran molecule up to 2000 kDa (hydrodynamic diameter 2.3 to 54.4 nm) at a 0.84 MPa acoustic pressure [45][22]. However, small opening (70 kDa) can be achieved by stable cavitation whereas larger BBB opening (>500 kDa) is associated with inertial cavitation. Thus, FUS has been demonstrated to markedly enhance the trans-BBB delivery of therapeutic antibodies (~150 kDa, e.g., Herceptin) [7,44[21][23][24][25][26],46,47,48], chemotherapeutics [49][27], and cells [50,51,52][28][29][30] and shows clinical promise in treating brain tumor and other CNS diseases [37,53][14][31]. Furthermore, studies indicate that FUS can be utilized to target therapeutics in different regions of the brain such as the hippocampus [54][32], striatum [55][33], cortical targets [46][24], and brainstem [49][27]. The safety of FUS-mediated BBB opening is promising. A mild and short term (<2 weeks) immune response is reported after repeated administration [56,57,58,59][34][35][36][37]. Importantly, behavioral, morphological, and neuroimaging characteristics are retained even after long-term repeated administration of FUS in animal models (biweekly over 6 months in rats or 4 months in non-human primates) [60,61][38][39].

2.3. Radiation-Mediated BBB Disruption

Few studies have reported that radiation therapy, an important modality in treating brain tumor, may play a role in disrupting the BBB and enhance drug entry to brain [62][40]. However, the role of radiation in increasing drug accumulation in brain and its underlying mechanisms are still uncertain. In addition, radiation induced BBB disruption is not temporary and the recovery time is much higher (in years) which often lead to radiation induced toxicity including headache, neurologic deficits or nausea [63][41].

2.4. Interfering the Tight Junction of BBB with Chemicals

Disengaging the tight junctions of BBB is another strategy to improve permeability across BBB. Bradykinin (BK), a peptide containing 9 aminoacids upon administration causes dilation of arterioles and enhances paracellular transport by down-regulating expression of the tight junction proteins (occluding, ZO-1, and claudin-5) and improves transcellular transport by upregulating caveolin mediated pinocytotic vesicles [64][42]. The BBB opening potential of bradykinin, and its synthetic analogs, have been explored [65,66,67][43][44][45] especially in brain tumors due to the high expression of BK receptor at BTB [68][46]. However, it did not go through Phase-II mainly because the extremely transient opening of BBB and the adverse side effects due to the wide distribution of BK receptors at numerous additional sites beyond the BBB [69][47]. BBB disruption via targeting claudin-5, a major component of BBB tight junctions, via siRNA mediated knockdown or using anti-claudin5-antibody also demonstrated to enhance BBB permeation transiently and reversibly [70,71][48][49]. It also suffers similar limitations of transient effects and adverse side effects due to wider distribution of receptor expression. To this end, targeting Angulin-1, another functional constituent of BBB tricellular tight junctions which is majorly expressed in BBB and selectively blocks entry of macromolecules into the brain, can address the adverse effects [72][50]. Angubindin-1, a ligand of angulin-1, is demonstrated to enhance the entry of macromolecules across BBB by removing angulin-1 and disrupting the tricellular tight junctions [73][51].

3. Drug Transport without Disrupting BBB: Active and Passive Transport Pathways

Recent strategies of drug delivery to brain without disrupting BBB can be classified into two types based on their energy (adenosine triphosphate (ATP)) requirements during the process: passive and active transport (Figure 43) [74][52]. Passive transport is an energy-independent process that lacks specificity. It includes the diffusion of small molecules through paracellular and transcellular pathways. Paracellular diffusion involves solute molecules moving between adjacent endothelial cells due to a negative concentration gradient. Only water-soluble molecules can pass through the paracellular space. In transcellular diffusion, non-ionic solute (molecular weight < 400 Da) with a desirable lipophilicity (e.g., hormones and steroids) can diffuse through the endothelial cells to brain [75][53]. However, in addition to the tight junction, some efflux pumps present at the luminal side of BCEC also limit the drug transport across BBB. Efflux pumps function in two phases, it initially inhibit cellular uptake of drug molecules in BCEC and later expel the drugs molecules (like doxorubicin, daunorubicin etc.) into blood against a negative concentration gradient in ATP dependent pathway [76][54]. P-glycoprotein (P-gp) is an example of efflux pump that plays a role in drug resistance in tumors. Regulating efflux pumps at the BBB represents another strategy for drug delivery to brain tumors. It is important to note that efflux pumps, although beneficial for protecting the healthy brain from harmful neurotoxins, can also pose challenges in drug delivery to brain tumors.
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Figure 43. Schematics for drug transport pathways across BBB.
The active transport pathway often exploits endogenous receptor or transporter proteins that are expressed on the luminal side of BBB. Active transport routes include receptor mediated transcytosis (RMT), carrier mediated transcytosis, adsorption-mediated transcytosis, and cell-mediated transcytosis, all of which require ATP. In RMT, particles cross BBB via interaction with specific receptors expressed on apical surface of BCEC. It is an important pathway and is widely being explored for delivery of macromolecular biopharmaceuticals (e.g., protein or recombinant peptide-based therapeutics) or nanocarrier-mediated drug transport to the brain. The mechanism of RMT centers on endocytosis, where a ligand selectively binds to a receptor. This binding leads to the creation of an intracellular vesicle through membrane invagination. These vesicles are then transported and fused with the basolateral membrane, subsequently releasing the payloads as they detach from the membrane. It is worth mentioning that, like general endocytosis, in addition to the transcytosis from blood to brain some vesicles undergo lysosomal degradation while some others are recycled to the apical side in RMT. This process often targets specific receptors, including transferrin receptors, low-density lipoprotein (LDL) receptors, and insulin receptors for drug delivery to the brain.
Carrier- or transporter- mediated transcytosis (CMT) represents another dynamic active transport mechanism across the BBB, facilitating the transportation of essential nutrients such as amino acids and glucose into the brain. Nutrient molecules bind to the specific transporter proteins on the luminal side, causing conformational changes that enable the transfer of these nutrients into the brain. Glucose transporter isoform (GLUT-1) and large amino-acid transporter (LAT) are examples of such transporter. Small molecule drugs like L-DOPA and gabapentin utilize CMT to reach the CNS. However, the high specificity required for the interaction between transporters and ligands in this process limits its applicability in transporting macromolecular therapeutics [77][55]. Charged particles such as nanocarriers, predominantly traverse the BBB through adsorptive mediated transcytosis (AMT), relying on the electrostatic interactions between the negatively charged cell surface of BCEC and the particles [78][56]. Such interactions are non-specific, and many nanocarriers can be delivered; however, this is not devoid of the non-specific accumulation in other organs under systemic circulation. Cell-mediated transcytosis, which utilizes blood cells capable of BBB crossing for delivering drug to brain, has recently emerged as biomimetic strategy. In this method, immune cells or platelets are incorporated with drug-loaded nanocarriers which then cross BBB and navigate towards the inflammation sites within the brain by responding to chemotaxis signals and undergoing diapedesis [79][57]. More recently, extracellular vesicles, e.g., exosomes, have attracted significant attention as biomimetic drug carrier for CNS drug delivery. In addition, viral vectors have shown promise for gene delivery to brain. Further nanocarrier-mediated approaches have gained significant interest for efficient delivery to brain.

3.1. Nanocarriers Mediated Drug Transport across BBB

Nanoparticles (NPs) such as liposomes, polymeric NPs, inorganic NPs, etc., are being used as drug carriers for decades [80,81,82,83,84,85][58][59][60][61][62][63]. Drug loading in NPs enhances circulation life of hydrophobic drugs in blood, protect nucleic-acid-based therapeutics from serum nucleases, or reduce the adverse off-target effects of drugs [86,87,88,89,90][64][65][66][67][68]. Surface of NPs can be engineered with PEG to achieve longer circulation life or with cell-penetrating peptide to enhance cellular uptake [91][69], or with targeting ligand to selectively deliver the payloads at targeted tissue [92][70]. Furthermore, drug release at the targeted tissue can be externally controlled by using stimuli-responsive nanocarriers [82][60]. Over the past few decades, many nanocarriers with size range ~10–300 nm have been explored for delivering small molecules, nucleotides, peptides, or proteins-based therapeutics to brain for combating various CNS diseases including brain tumor, neurodegenerative disorders, neuroHIV, stroke, etc. [82,88,89,90,93,94,95,96,97,98,99,100,101,102,103][60][66][67][68][71][72][73][74][75][76][77][78][79][80][81]. Such nanocarriers can cross the BBB by passive diffusion or can be engineered with some ligand at their exo-surfaces actively targeting some endogenous receptor/transporter protein on the BBB. For instance, liposomal encapsulation of cytotoxic anti-neoplastic agent doxorubicin has significantly mitigated the adverse effect of systemic chemotherapy as indicated by the enhanced safety index in a phase I trial involving 13 children with recurrent/refractory high-grade glioma (NCT02861222) [104][82]. Similarly, liposomal encapsulation of irinotecan has improved the safety profile of systemic chemotherapy in another phase I study with 34 high-grade glioma patients (NCT02022644) permitting its progression for Phase II trial [105][83]. However, although such encapsulation of cytotoxic chemotherapeutics improved the safety index of systemic chemotherapy in patients, the efficacy of nanoformulations might be facilitated by their passive accumulation via compromised integrity of the BBB around high-grade tumors. Clearly, there is a need for an active transport mechanism across the BBB for delivering drugs to combat low-grade tumor or other CNS diseases with intact or less compromised integrity of BBB.
Active targeting of receptor or transporter proteins expressed in brain capillary endothelial cells (BCEC) is the most widely explored nanocarrier-based drug delivery strategy across BBB. In this method, nanocarriers are surface engineered with targeting ligands of such receptors/transporters to deliver payload in brain via RMT or CMT which has been reviewed elsewhere in detail [106,107][84][85]. Although Transferrin, LDL family receptors (LDLR), insulin, and integrin receptors are widely explored receptors due to their high receptor-ligand affinity, GLUT and LAT-1 are some transporter proteins that are explored for drug delivery to brain.
Transferrin Receptor: Transferrin receptors (TfRs) control iron homeostasis via their natural ligand transferrin. TfRs are highly expressed in the luminal side of BBB and in brain tumors which makes them an attractive target for drug delivery to the brain [108][86]. Different TfRs ligands such as transferrin (Tf) itself (~80 kDa) [109][87], antibodies or antibody fragments [110][88], and peptides [111,112][89][90] are explored to examine their brain targeting efficacy by grafting such ligands with the biopharmaceuticals or at the exo-surface of nanocarriers which is reviewed in detail elsewhere [113][91]. For instance, Lam et al. have developed a transferrin-functionalized PEGylated liposomes for simultaneous delivery of temozolomide (TMZ) and bromodomain inhibitor in brain tumor. The combined chemotherapy regimen overcome the drug resistance of TMZ, reduced the tumor size, and improved the survival of mice with glioma compared to control groups, all while showing minimal systemic drug toxicity [109][87]. To overcome the plausible inhibition of RMT by competitive binding of endogenous Tf, nanocarriers are also surface engineered with monoclonal antibody (mAb), or peptide fragments targeting TfR. For instance, Yue et al. has conjugated OX26 antibody, a monoclonal antibody against TfR1, with micelles to develop an immunomicelle which shows high BBB-crossing ability [110][88]. A TfR specific heptapeptide T7 (HAIYPRH) with high binding affinity (Kd = 10 nM) has also been explored to target nucleotides and neoplastic drugs in glioma tissue in preclinical model [111,112][89][90]. Although such studies are at the preclinical stages, some have shown initial clinical promise [95][73]. For instance, a fusion of lysosomal enzyme iduronate 2- sulfatase (IDS) with anti- TfR antibody (JR-141) enabled successful delivery of the fusion protein into the CNS of patients with Hunter Syndrome under systemic settings (i.v.) in a phase I/II trial (NCT03128593) which shows promising therapeutic efficacy with no significant safety issue [114][92]. Notably, the use of TfR-targeting Tf-toxin conjugates has demonstrated clinical potential in anti-glioma therapy. Human Tf is linked to a diphtheria toxin featuring a CRM107 point mutation, resulting in the creation of Tf-CRM107. This conjugate displayed tumor growth inhibition when administered directly into the tumor in a U251 mouse model [115][93]. Subsequently, a phase I study following intra-tumoral injection revealed no adverse effects, leading to a phase II study involving patients with recurrent high-grade brain tumors. Although 35% of the patients displayed positive tumor responses and improved survival, the phase III was discontinued due to probable CNS toxicity with an indication for more targeted delivery of the toxin [116][94].
The sub-optimal clinical efficiency of TfRs targeting may be related to the high recycling rate (~90%) of endocytosed TfRs by BCEC to the luminal side as indicated by studies in mouse brain [117][95] where only 10% of TfR-NPs are able to reach brain parenchyma. Efforts to improve rate of transcytosis via varying ligand density on nanocarrier [118][96] or increasing receptor-ligand affinity are being examined [119][97]. Bivalent TfR antibodies with high receptor-affinity diverts the trafficking into lysosomes and subsequent degradation of the therapeutics indicating requirement of optimum receptor-ligand affinity for effective transcytosis [120,121][98][99]. Furthermore, interspecies variation of receptors, such as 2.5 times higher expression level of TfRs in mouse brain microvessels compared with that in human also contributes to the reduced efficacy during clinical translation of such active targeting strategies. Finally, ubiquitous expression of TfRs in other organs (liver, spleen, and bone-marrow) and uptakes of drugs in non-peripheral tissues also contribute to the compromised therapeutic efficacy of such targeting strategy [118][96].

3.2. Magnetic Field Assisted Crossing of BBB

Application of an external magnetic field is another physical method for drug delivery to the brain which not only spatially guides the magnetic nanoparticle to the targeted region but also significantly improves the speed and time for drug delivery. In this method, paramagnetic nanoparticles (PMNP), especially superparamagnetic iron oxide nanoparticles (SPIONs) with sizes ~10–100 nm, are used. Although magnetic nanoparticles (MNPs) and liposomes in diameters of 70 nm do not cross the BBB, the application of a static magnetic field facilitates its delivery across BBB. Particle size controls the magnetic susceptibility under a fixed static magnetic field. Small SPIONs exhibit higher magnetic susceptibility (highest with crystalline domain with 10–30 nm) than larger paramagnetic nanoparticles containing many crystalline domains mutually diminish the net magnetic moment. In addition, nanoparticles of 10–100 nm are considered optimum due to their longer systemic circulation times. The size of the nanoparticles determines their effect on BBB. For instance, SPION with ~117 nm under 0.39 Tesla did not disrupt BBB integrity whereas magnetic nanoparticles with a size of 800 nm cause leakage in BBB under the same magnetic field strength. In addition, the lower particle size with higher magnetic susceptibility requires less field strength, although no adverse effect in cells is reported with the static magnetic field as strong as up to 10 Tesla. Although the transcellular migration through BCEC via uptake or nanoporation is presumed to be the major pathway, some recent studies indicate interaction of SPIONs with junction proteins such as VE-cadherin may contribute to additional involvement of the paracellular pathway for BBB crossing [148,149][100][101].
SPIONs are used in clinics for MRI as a contrast agent and hold potential for other biomedical purposes including targeted drug delivery, image-guided drug delivery, hyperthermia, etc., for the management of CNS diseases [96,150,151][74][102][103]. SPIONs can be surface-functionalized with different polymers, lipids etc. to achieve desired drug loading or pharmacokinetic property. For instance, polystyrene-coated SPIONs (~100 nm) under 0.1 T external magnetic field cross the BBB, accumulate in the brain parenchyma, and exhibit 25 times greater retention with minimal neurotoxicity. Similarly, transferrin-coated PEGylated magneto liposomes (~130 nm) exhibit complete transmigration across an in vitro BBB under 0.08 T magnetic field without affecting the BBB [152][104]. Beyond small molecule anti-cancer drugs [150][102], magneto liposomes also have been used to facilitate delivery of therapeutic peptide [153][105], brain-derived neurotrophic factor (BDNF) [154][106] or antiretroviral agents across the BBB [155,156][107][108]. For instance, to enhance the BBB permeation of antiretroviral agent 3′Azido-3′deoxythymidine-5′-triphosphate (AZT), it is complexed with SPIONs (~25 nm) followed by coating with liposome. This magneto liposome containing encapsulated AZT (~150 nm) crosses the BBB (in vitro) under 0.3 T field and results in three times higher accumulation of AZT across BBB compared to the only AZT [155][107]. Importantly, to further gain control for on-demand drug release, MNP are modified to electromagnetic nanoparticles (MENP) [157][109] which exhibit brain accumulation under low ac magnetic field with no adverse effect in rodents [158][110] and non-human primates [159][111] and can facilitate delivery of hydrophilic therapeutics including siRNA [160][112], CRISPR [161][113] across in vitro BBB (Figure 54). It is worth mentioning that such MENP can also be used for non-invasive deep brain stimulation to control neuroactivity in Parkinson’s disease [162][114]. Many studies have claimed lysosomal degradation of SPIONs as histopathological evaluation of major organs involved in systemic circulation revealed no iron-positive pigment or related macrophage accumulation [158,163][110][115]. However, some recent studies have reported toxicity of SPIONs as it causes an imbalance in iron homeostasis which may induce oxidative stress and inflammation leading to genotoxicity due to its differential interaction with mitochondria [164,165][116][117]. Clearly, in-depth evaluation of in vivo toxicity in long-term exposure to SPION is needed.
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Figure 54. Magnetic field assisted drug delivery to the brain: (A) TEM of a magneto electric nanoparticle (MENP) containing CoFe2O4 at the core with a shell of BaTiO3 (B) which enables controlled drug release under alternating electric stimuli, (C) MENP (~30 nm) can be loaded with CRISPR via hydrophilic interaction which allows their non-invasive delivery across BBB (in vitro) under electromagnetic field, (D) TEM of brain tissue from (i) untreated mice and (ii) mice intravenously administered with 10 mg/kg BW of MENP indicating brain accumulation of MENP (black dot in D(ii)). (E) Schematic for potential simultaneous delivery of hydrophilic and hydrophobic payload to the brain using MENP-liposome composed of a lipid coating embedded with hydrophobic drug onto the hydrophilic drug-loaded MENP. Adopted with permission from Refs. [148,157,158,161][100][109][110][113].

3.3. Cell-Based Biomimetic Strategy of BBB Crossing

Bioinspired carriers such as blood cells, cell-membrane-coated nanocarriers, exosomes, etc., are being explored recently for drug delivery across BBB due to their longer circulation life and biocompatibility [79][57]. Leukocytes such as macrophages, monocytes, and neutrophils are most explored for brain delivery due to their inherent chemotactic recruitment property, especially brain diseases with inflammation. In such methods, drugs are first loaded in nanocarriers which are then incorporated into cells to facilitate delivery across the BBB. For instance, Xue et al. have used neutrophils to deliver paclitaxel loaded liposomes in residual tissue post-surgery which have suppressed the recurrence of glioma growth [166][118]. To treat ischemic stroke, Xu et al. have developed a ‘nanoplatelet’ by coating a neuroprotective agent loaded dextran-based nanocarrier with platelet membrane surface-engineered with thrombin-responsive anti-ischemic drug and TAT peptide. This ‘nanoplatelet’ crosses the BBB, clears the thrombus clog at the ischemic site in the brain and delivers neuroprotective agent to combat ischemic stroke [167][119]. In another study, to combat encephalitis Yuan et al. have utilized a macrophage-derived exosome for delivering brain-derived neurotrophic factor (BDNF) to inflamed brain [168][120]. Such BDNF-loaded exosomes crosses BBB via intercellular adhesion molecule 1 (ICAM-1) which is upregulated under encephalitis-related inflammation. However, cell-based carriers suffer from some common limitations such as viability of cell-based carriers arising due to leaching of drug from nanocarriers. In addition, there are some cell-specific limitations like risk of immune activation while using leukocytes or activation of platelets while using it as drug carrier that may cause undesired thrombosis or bleeding. Exosomes are extracellular vesicles which show ~0.5% passive brain accumulation and have attracted attention for drug delivery to brain and treating neurological conditions. For instance, i.v. administration of dopamine-loaded exosomes enhanced the dopamine levels (15 times) in mouse brain [169][121]. Further understanding of the interaction between the BBB and bio-mimetic carriers are necessary for proper engineering of such carrier to maximize therapeutic benefit. Extracellular vesicles (EVs) derived from the cells have been explored for neuroprotective applications including traumatic brain injury. In one example, the EVs derived from mesenchymal stromal cells (MSCs) were examined from neuronal cell protection using in vitro models [170][122].

References

  1. Rapoport, S.; Hori, M.; Klatzo, I. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am. J. Physiol. Content 1972, 223, 323–331.
  2. Brightman, M.W.; Hori, M.; Rapoport, S.I.; Reese, T.S.; Westergaard, E. Osmotic opening of tight junctions in cerebral endothelium. J. Comp. Neurol. 1973, 152, 317–325.
  3. Karmur, B.S.; Philteos, J.; Abbasian, A.; Zacharia, B.E.; Lipsman, N.; Levin, V.; Grossman, S.; Mansouri, A. Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome. Front. Oncol. 2020, 10, 563840.
  4. Neuwelt, E.A.; Goldman, D.L.; Dahlborg, S.A.; Crossen, J.; Ramsey, F.; Roman-Goldstein, S.; Braziel, R.; Dana, B. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: Prolonged survival and preservation of cognitive function. J. Clin. Oncol. 1991, 9, 1580–1590.
  5. Williams, P.C.; Henner, W.D.; Roman-Goldstein, S.; Dahlborg, S.A.; Brummett, R.E.; Tableman, M.; Dana, B.W.; Neuwelt, E.A. Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms. Neurosurgery 1995, 37, 17–27; Discussion 27–28.
  6. Burks Scott, R.; Kersch Cymon, N.; Witko Jaclyn, A.; Pagel Michael, A.; Sundby, M.; Muldoon Leslie, L.; Neuwelt Edward, A.; Frank Joseph, A. Blood–brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses. Proc. Natl. Acad. Sci. USA 2021, 118, e2021915118.
  7. Kemper, E.M.; Boogerd, W.; Thuis, I.; Beijnen, J.H.; van Tellingen, O. Modulation of the blood-brain barrier in oncology: Therapeutic opportunities for the treatment of brain tumours? Cancer Treat. Rev. 2004, 30, 415–423.
  8. Boockvar, J.A.; Tsiouris, A.J.; Hofstetter, C.P.; Kovanlikaya, I.; Fralin, S.; Kesavabhotla, K.; Seedial, S.M.; Pannullo, S.C.; Schwartz, T.H.; Stieg, P.; et al. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article. J. Neurosurg. 2011, 114, 624–632.
  9. Chu, C.; Liu, G.; Janowski, M.; Bulte, J.W.M.; Li, S.; Pearl, M.; Walczak, P. Real-Time MRI Guidance for Reproducible Hyperosmolar Opening of the Blood-Brain Barrier in Mice. Front. Neurol. 2018, 9, 921.
  10. Janowski, M.; Walczak, P.; Pearl, M.S. Predicting and optimizing the territory of blood–brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance. J. Cereb. Blood Flow Metab. 2015, 36, 569–575.
  11. Hynynen, K.; McDannold, N.; Vykhodtseva, N.; Jolesz, F.A. Noninvasive MR imaging–guided focal opening of the blood-brain barrier in rabbits. Radiology 2001, 220, 640–646.
  12. Hynynen, K.; McDannold, N.; Vykhodtseva, N.; Jolesz, F.A. Non-invasive opening of BBB by focused ultrasound. Acta Neurochir. Suppl. 2003, 86, 555–558.
  13. Hynynen, K.; McDannold, N.; Sheikov, N.A.; Jolesz, F.A.; Vykhodtseva, N. Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. NeuroImage 2005, 24, 12–20.
  14. Meng, Y.; Hynynen, K.; Lipsman, N. Applications of focused ultrasound in the brain: From thermoablation to drug delivery. Nat. Rev. Neurol. 2020, 17, 7–22.
  15. Sheikov, N.; McDannold, N.; Vykhodtseva, N.; Jolesz, F.; Hynynen, K. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med. Biol. 2004, 30, 979–989.
  16. van Wamel, A.; Kooiman, K.; Emmer, M.; Cate, F.T.; Versluis, M.; de Jong, N. Ultrasound microbubble induced endothelial cell permeability. J. Control. Release 2006, 116, e100–e102.
  17. McDannold, N.; Vykhodtseva, N.; Hynynen, K. Targeted disruption of the blood–brain barrier with focused ultrasound: Association with cavitation activity. Phys. Med. Biol. 2006, 51, 793–807.
  18. Jalali, S.; Huang, Y.; Dumont, D.J.; Hynynen, K. Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: Experimental study in rats. BMC Neurol. 2010, 10, 114.
  19. McDannold, N.; Vykhodtseva, N.; Hynynen, K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med. Biol. 2008, 34, 930–937.
  20. Wu, S.-K.; Chu, P.-C.; Chai, W.-Y.; Kang, S.-T.; Tsai, C.-H.; Fan, C.-H.; Yeh, C.-K.; Liu, H.-L. Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening. Sci. Rep. 2017, 7, srep46689.
  21. Kinoshita, M.; McDannold, N.; Jolesz, F.A.; Hynynen, K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood–brain barrier disruption. Proc. Natl. Acad. Sci. USA 2006, 103, 11719–11723.
  22. Chen, H.; Konofagou, E.E. The size of blood–brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. J. Cereb. Blood Flow Metab. 2014, 34, 1197–1204.
  23. Cadavid, D.; Jurgensen, S.; Lee, S. Impact of natalizumab on ambulatory improvement in secondary progressive and disabled relapsing-remitting multiple sclerosis. PLoS ONE 2013, 8, e53297.
  24. Jordão, J.F.; Ayala-Grosso, C.A.; Markham, K.; Huang, Y.; Chopra, R.; McLaurin, J.; Hynynen, K.; Aubert, I. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease. PLoS ONE 2010, 5, e10549.
  25. Kobus, T.; Zervantonakis, I.K.; Zhang, Y.; McDannold, N.J. Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption. J. Control. Release 2016, 238, 281–288.
  26. Alecou, T.; Giannakou, M.; Damianou, C. Amyloid β Plaque Reduction With Antibodies Crossing the Blood-Brain Barrier, Which Was Opened in 3 Sessions of Focused Ultrasound in a Rabbit Model. J. Ultrasound Med. 2017, 36, 2257–2270.
  27. Alli, S.; Figueiredo, C.A.; Golbourn, B.; Sabha, N.; Wu, M.Y.; Bondoc, A.; Luck, A.; Coluccia, D.; Maslink, C.; Smith, C.; et al. Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery. J. Control. Release 2018, 281, 29–41.
  28. Burgess, A.; Ayala-Grosso, C.A.; Ganguly, M.; Jordão, J.F.; Aubert, I.; Hynynen, K. Targeted delivery of neural stem cells to the brain using MRI-guided focused ultrasound to disrupt the blood-brain barrier. PLoS ONE 2011, 6, e27877.
  29. Alkins, R.; Burgess, A.; Ganguly, M.; Francia, G.; Kerbel, R.; Wels, W.S.; Hynynen, K. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res. 2013, 73, 1892–1899.
  30. Alkins, R.; Burgess, A.; Kerbel, R.; Wels, W.S.; Hynynen, K. Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival. Neuro-Oncology 2016, 18, 974–981.
  31. Arif, W.M.; Elsinga, P.H.; Gasca-Salas, C.; Versluis, M.; Martínez-Fernández, R.; Dierckx, R.A.; Borra, R.J.; Luurtsema, G. Focused ultrasound for opening blood-brain barrier and drug delivery monitored with positron emission tomography. J. Control. Release 2020, 324, 303–316.
  32. Thévenot, E.; Jordão, J.F.; O’Reilly, M.A.; Markham, K.; Weng, Y.-Q.; Foust, K.D.; Kaspar, B.K.; Hynynen, K.; Aubert, I. Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum. Gene Ther. 2012, 23, 1144–1155.
  33. Noroozian, Z.; Xhima, K.; Huang, Y.; Kaspar, B.K.; Kügler, S.; Hynynen, K.; Aubert, I. MRI-Guided Focused Ultrasound for Targeted Delivery of rAAV to the Brain. Methods Mol Biol. 2019, 1950, 177–197.
  34. Kovacs, Z.I.; Kim, S.; Jikaria, N.; Qureshi, F.; Milo, B.; Lewis, B.K.; Bresler, M.; Burks, S.R.; Frank, J.A. Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation. Proc. Natl. Acad. Sci. USA 2016, 114, E75–E84.
  35. Poon, C.T.; Shah, K.; Lin, C.; Tse, R.; Kim, K.K.; Mooney, S.; Aubert, I.; Stefanovic, B.; Hynynen, K. Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease. Sci. Rep. 2018, 8, 14061.
  36. McMahon, D.; Bendayan, R.; Hynynen, K. Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome. Sci. Rep. 2017, 7, srep45657.
  37. McMahon, D.; Hynynen, K. Acute Inflammatory Response Following Increased Blood-Brain Barrier Permeability Induced by Focused Ultrasound is Dependent on Microbubble Dose. Theranostics 2017, 7, 3989–4000.
  38. Olumolade, O.O.; Wang, S.; Samiotaki, G.; Konofagou, E.E. Longitudinal Motor and Behavioral Assessment of Blood–Brain Barrier Opening with Transcranial Focused Ultrasound. Ultrasound Med. Biol. 2016, 42, 2270–2282.
  39. Horodyckid, C.; Canney, M.; Vignot, A.; Boisgard, R.; Drier, A.; Huberfeld, G.; François, C.; Prigent, A.; Santin, M.D.; Adam, C.; et al. Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: A multiparametric study in a primate model. J. Neurosurg. 2017, 126, 1351–1361.
  40. Miller, M.A.; Chandra, R.; Cuccarese, M.F.; Pfirschke, C.; Engblom, C.; Stapleton, S.; Adhikary, U.; Kohler, R.H.; Mohan, J.F.; Pittet, M.J.; et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 2017, 9, eaal0225.
  41. van Vulpen, M.; Kal, H.B.; Taphoorn, M.J.; El Sharouni, S.Y. Changes in blood-brain barrier permeability induced by radiotherapy: Implications for timing of chemotherapy? (Review). Oncol. Rep. 2002, 9, 683–688.
  42. Liu, L.B.; Xue, Y.X.; Liu, Y.H. Bradykinin increases the permeability of the blood-tumor barrier by the caveolae-mediated transcellular pathway. J. Neuro-Oncol. 2010, 99, 187–194.
  43. Sanovich, E.; Bartus, R.T.; Friden, P.M.; Dean, R.L.; Le, H.Q.; Brightman, M.W. Pathway across blood-brain barrier opened by the bradykinin agonist, RMP-7. Brain Res. 1995, 705, 125–135.
  44. Emerich, D.F.; Snodgrass, P.; Pink, M.; Bloom, F.; Bartus, R.T. Central analgesic actions of loperamide following transient permeation of the blood brain barrier with Cerepor (RMP-7). Brain Res. 1998, 801, 259–266.
  45. Black, K.L.; Cloughesy, T.; Huang, S.-C.; Gobin, Y.P.; Zhou, Y.; Grous, J.; Nelson, G.; Farahani, K.; Hoh, C.K.; Phelps, M.; et al. Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas. J. Neurosurg. 1997, 86, 603–609.
  46. Inamura, T.; Black, K.L. Bradykinin selectively opens blood-tumor barrier in experimental brain tumors. J. Cereb. Blood Flow Metab. 1994, 14, 862–870.
  47. Han, L. Modulation of the Blood–Brain Barrier for Drug Delivery to Brain. Pharmaceutics 2021, 13, 2024.
  48. Campbell, M.; Kiang, A.-S.; Kenna, P.F.; Kerskens, C.; Blau, C.; O’Dwyer, L.; Tivnan, A.; Kelly, J.A.; Brankin, B.; Farrar, G.-J.; et al. RNAi-mediated reversible opening of the blood-brain barrier. J. Gene Med. 2008, 10, 930–947.
  49. Campbell, M.; Hanrahan, F.; Gobbo, O.L.; Kelly, M.E.; Kiang, A.-S.; Humphries, M.M.; Nguyen, A.T.; Ozaki, E.; Keaney, J.; Blau, C.W.; et al. Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury. Nat. Commun. 2012, 3, 849.
  50. Krug, S.M.; Hayaishi, T.; Iguchi, D.; Watari, A.; Takahashi, A.; Fromm, M.; Nagahama, M.; Takeda, H.; Okada, Y.; Sawasaki, T.; et al. Angubindin-1, a novel paracellular absorption enhancer acting at the tricellular tight junction. J. Control. Release 2017, 260, 1–11.
  51. Zeniya, S.; Kuwahara, H.; Daizo, K.; Watari, A.; Kondoh, M.; Yoshida-Tanaka, K.; Kaburagi, H.; Asada, K.; Nagata, T.; Nagahama, M.; et al. Angubindin-1 opens the blood–brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system. J. Control. Release 2018, 283, 126–134.
  52. Pardridge, W.M. Drug transport across the blood–brain barrier. J. Cereb. Blood Flow Metab. 2012, 32, 1959–1972.
  53. Burek, M.; Förster, C.Y. Culturing of Rodent Brain Microvascular Endothelial Cells for In Vitro Modeling of the Blood-Brain Barrier. In Blood-Brain Barrier; Barichello, T., Ed.; Springer: New York, NY, USA, 2019; pp. 45–54.
  54. Mahringer, A.; Ott, M.; Reimold, I.; Reichel, V.; Fricker, G. The ABC of the blood-brain barrier-regulation of drug efflux pumps. Curr. Pharm. Des. 2011, 17, 2762–2770.
  55. Puris, E.; Gynther, M.; Auriola, S.; Huttunen, K.M. L-Type amino acid transporter 1 as a target for drug delivery. Pharm. Res. 2020, 37, 88.
  56. Lu, W. Adsorptive-mediated brain delivery systems. Curr. Pharm. Biotechnol. 2012, 13, 2340–2348.
  57. Li, Y.-J.; Wu, J.-Y.; Liu, J.; Qiu, X.; Xu, W.; Tang, T.; Xiang, D.-X. From blood to brain: Blood cell-based biomimetic drug delivery systems. Drug Deliv. 2021, 28, 1214–1225.
  58. Shi, J.; Kantoff, P.W.; Wooster, R.; Farokhzad, O.C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2017, 17, 20–37.
  59. Marrache, S.; Pathak, R.; Darley, K.; Choi, J.; Zaver, D.; Kolishetti, N.; Dhar, S. Nanocarriers for Tracking and Treating Diseases. Curr. Med. Chem. 2013, 20, 3500–3514.
  60. Kolishetti, N.; Vashist, A.; Arias, A.Y.; Atluri, V.; Dhar, S.; Nair, M. Recent advances, status, and opportunities of magneto-electric nanocarriers for biomedical applications. Mol. Asp. Med. 2021, 83, 101046.
  61. Kolishetti, N.; Alexis, F.; Pridgen, E.M.; Farokhzad, O.C. Chapter 4: Biodistribution and Pharmacokinetics of Nanoprobes. In Nanoplatform-Based Molecular Imaging; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011; pp. 75–104.
  62. Pathak, R.K.; Kolishetti, N.; Dhar, S. Targeted nanoparticles in mitochondrial medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2014, 7, 315–329.
  63. Feldhaeusser, B.; Platt, S.R.; Marrache, S.; Kolishetti, N.; Pathak, R.K.; Montgomery, D.J.; Reno, L.R.; Howerth, E.; Dhar, S. Evaluation of nanoparticle delivered cisplatin in beagles. Nanoscale 2015, 7, 13822–13830.
  64. Bhunia, S.; Radha, V.; Chaudhuri, A. CDC20siRNA and paclitaxel co-loaded nanometric liposomes of a nipecotic acid-derived cationic amphiphile inhibit xenografted neuroblastoma. Nanoscale 2016, 9, 1201–1212.
  65. Bhunia, S.; Jaiswal, M.K.; Singh, K.A.; Deo, K.A.; Gaharwar, A.K. 2D Covalent Organic Framework Direct Osteogenic Differentiation of Stem Cells. Adv. Health Mater. 2022, 11, 2101737.
  66. Surnar, B.; Basu, U.; Banik, B.; Ahmad, A.; Marples, B.; Kolishetti, N.; Dhar, S. Nanotechnology-mediated crossing of two impermeable membranes to modulate the stars of the neurovascular unit for neuroprotection. Proc. Natl. Acad. Sci. USA 2018, 115, E12333–E12342.
  67. Kolb, D.; Kolishetti, N.; Surnar, B.; Sarkar, S.; Guin, S.; Shah, A.S.; Dhar, S. Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration. ACS Nano 2020, 14, 11055–11066.
  68. Surnar, B.; Shah, A.S.; Park, M.; Kalathil, A.A.; Kamran, M.Z.; Jaime, R.R.; Toborek, M.; Nair, M.; Kolishetti, N.; Dhar, S. Brain-Accumulating Nanoparticles for Assisting Astrocytes to Reduce Human Immunodeficiency Virus and Drug Abuse-Induced Neuroinflammation and Oxidative Stress. ACS Nano 2021, 15, 15741–15753.
  69. Majumder, P.; Bhunia, S.; Chaudhuri, A. A lipid-based cell penetrating nano-assembly for RNAi-mediated anti-angiogenic cancer therapy. Chem. Commun. 2018, 54, 1489–1492.
  70. Pathak, R.K.; Basu, U.; Ahmad, A.; Sarkar, S.; Kumar, A.; Surnar, B.; Ansari, S.; Wilczek, K.; Ivan, M.E.; Marples, B.; et al. A designer bow-tie combination therapeutic platform: An approach to resistant cancer treatment by simultaneous delivery of cytotoxic and anti-inflammatory agents and radiation. Biomaterials 2018, 187, 117–129.
  71. Ding, S.; Khan, A.I.; Cai, X.; Song, Y.; Lyu, Z.; Du, D.; Dutta, P.; Lin, Y. Overcoming blood–brain barrier transport: Advances in nanoparticle-based drug delivery strategies. Mater. Today 2020, 37, 112–125.
  72. Zhou, Y.; Peng, Z.; Seven, E.S.; Leblanc, R.M. Crossing the blood-brain barrier with nanoparticles. J. Control. Release 2017, 270, 290–303.
  73. Terstappen, G.C.; Meyer, A.H.; Bell, R.D.; Zhang, W. Strategies for delivering therapeutics across the blood–brain barrier. Nat. Rev. Drug Discov. 2021, 20, 362–383.
  74. Nair, M.; Jayant, R.D.; Kaushik, A.; Sagar, V. Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. Adv. Drug Deliv. Rev. 2016, 103, 202–217.
  75. Sarmah, D.; Banerjee, M.; Datta, A.; Kalia, K.; Dhar, S.; Yavagal, D.R.; Bhattacharya, P. Nanotechnology in the diagnosis and treatment of stroke. Drug Discov. Today 2020, 26, 585–592.
  76. Mamo, T.; Moseman, E.A.; Kolishetti, N.; Morales, C.S.; Shi, J.; Kuritzkes, D.R.; Langer, R.; von Andrian, U.; Farokhzad, O.C. Emerging nanotechnology approaches HIV/AIDS treatment and prevention. Nanomedicine 2010, 5, 269–285.
  77. Varlamova, E.G.; Turovsky, E.A.; Blinova, E.V. Therapeutic Potential and Main Methods of Obtaining Selenium Nanoparticles. Int. J. Mol. Sci. 2021, 22, 10808.
  78. Varlamova, E.G.; Baryshev, A.S.; Gudkov, S.V.; Babenko, V.A.; Plotnikov, E.Y.; Turovsky, E.A. Cerium Oxide Nanoparticles Protect Cortical Astrocytes from Oxygen–Glucose Deprivation through Activation of the Ca2+ Signaling System. Int. J. Mol. Sci. 2023, 24, 14305.
  79. Vashist, A.; Raymond, A.D.; Chapagain, P.; Vashist, A.; Arias, A.Y.; Kolishetti, N.; Nair, M. Multi-functional auto-fluorescent nanogels for theranostics. J. NeuroVirol. 2023, 29, 252–257.
  80. Vashist, A.; Manickam, P.; Raymond, A.D.; Arias, A.Y.; Kolishetti, N.; Vashist, A.; Arias, E.; Nair, M. Recent Advances in Nanotherapeutics for Neurological Disorders. ACS Appl. Bio Mater. 2023, 6, 2614–2621.
  81. Tomitaka, A.; Vashist, A.; Kolishetti, N.; Nair, M. Machine learning assisted-nanomedicine using magnetic nanoparticles for central nervous system diseases. Nanoscale Adv. 2023, 5, 4354–4367.
  82. Chastagner, P.; Devictor, B.; Geoerger, B.; Aerts, I.; Leblond, P.; Frappaz, D.; Gentet, J.C.; Bracard, S.; André, N. Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma. Cancer Chemother. Pharmacol. 2015, 76, 425–432.
  83. Clarke, J.L.; Molinaro, A.M.; Cabrera, J.R.; DeSilva, A.A.; Rabbitt, J.E.; Prey, J.; Drummond, D.C.; Kim, J.; Noble, C.; Fitzgerald, J.B.; et al. A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma. Cancer Chemother. Pharmacol. 2017, 79, 603–610.
  84. Bhunia, S.; Chaudhuri, A. Crossing Blood-Brain Barrier with Nano-drug Carriers for Treatment of Brain Tumors: Advances and Unmet Challenges. In Brain Tumors; IntechOpen: London, UK, 2022.
  85. Yeini, E.; Ofek, P.; Albeck, N.; Ajamil, D.R.; Neufeld, L.; Eldar-Boock, A.; Kleiner, R.; Vaskovich, D.; Koshrovski-Michael, S.; Dangoor, S.I.; et al. Targeting Glioblastoma: Advances in Drug Delivery and Novel Therapeutic Approaches. Adv. Ther. 2020, 4, 2000124.
  86. Shir, A.; Levitzki, A. Inhibition of glioma growth by tumor-specific activation of double-stranded RNA-dependent protein kinase PKR. Nat. Biotechnol. 2002, 20, 895–900.
  87. Lam, F.C.; Morton, S.W.; Wyckoff, J.; Han, T.-L.V.; Hwang, M.K.; Maffa, A.; Balkanska-Sinclair, E.; Yaffe, M.B.; Floyd, S.R.; Hammond, P.T. Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nat. Commun. 2018, 9, 1991.
  88. Yue, J.; Liu, S.; Wang, R.; Hu, X.; Xie, Z.; Huang, Y.; Jing, X. Fluorescence-labeled immunomicelles: Preparation, in vivo biodistribution, and ability to cross the blood-brain barrier. Macromol. Biosci. 2012, 12, 1209–1219.
  89. Liu, S.; Guo, Y.; Huang, R.; Li, J.; Huang, S.; Kuang, Y.; Han, L.; Jiang, C. Gene and doxorubicin co-delivery system for targeting therapy of glioma. Biomaterials 2012, 33, 4907–4916.
  90. Kuang, Y.; An, S.; Guo, Y.; Huang, S.; Shao, K.; Liu, Y.; Li, J.; Ma, H.; Jiang, C. T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting. Int. J. Pharm. 2013, 454, 11–20.
  91. Koneru, T.; McCord, E.; Pawar, S.; Tatiparti, K.; Sau, S.; Iyer, A.K. Transferrin: Biology and Use in Receptor-Targeted Nanotherapy of Gliomas. ACS Omega 2021, 6, 8727–8733.
  92. Okuyama, T.; Eto, Y.; Sakai, N.; Minami, K.; Yamamoto, T.; Sonoda, H.; Yamaoka, M.; Tachibana, K.; Hirato, T.; Sato, Y. Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1/2 Trial. Mol. Ther. 2019, 27, 456–464.
  93. Laske, D.W.; Ilercil, O.; Akbasak, A.; Youle, R.J.; Oldfield, E.H. Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J. Neurosurg. 1994, 80, 520–526.
  94. Weaver, M.; Laske, D.W. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J. Neuro-Oncol. 2003, 65, 3–14.
  95. Roberts, R.L.; Fine, R.E.; Sandra, A. Receptor-mediated endocytosis of transferrin at the blood-brain barrier. J. Cell Sci. 1993, 104 Pt 2, 521–532.
  96. Johnsen, K.B.; Bak, M.; Melander, F.; Thomsen, M.S.; Burkhart, A.; Kempen, P.J.; Andresen, T.L.; Moos, T. Modulating the antibody density changes the uptake and transport at the blood-brain barrier of both transferrin receptor-targeted gold nanoparticles and liposomal cargo. J. Control. Release 2019, 295, 237–249.
  97. Yu, Y.J.; Zhang, Y.; Kenrick, M.; Hoyte, K.; Luk, W.; Lu, Y.; Atwal, J.; Elliott, J.M.; Prabhu, S.; Watts, R.J.; et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Transl. Med. 2011, 3, 84ra44.
  98. Bien-Ly, N.; Yu, Y.J.; Bumbaca, D.; Elstrott, J.; Boswell, C.A.; Zhang, Y.; Luk, W.; Lu, Y.; Dennis, M.S.; Weimer, R.M.; et al. Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 2014, 211, 233–244.
  99. Gadkar, K.; Yadav, D.B.; Zuchero, J.Y.; Couch, J.A.; Kanodia, J.; Kenrick, M.K.; Atwal, J.K.; Dennis, M.S.; Prabhu, S.; Watts, R.J.; et al. Mathematical PKPD and safety model of bispecific TfR/BACE1 antibodies for the optimization of antibody uptake in brain. Eur. J. Pharm. Biopharm. 2016, 101, 53–61.
  100. Kaushik, A.; Nikkhah-Moshaie, R.; Sinha, R.; Bhardwaj, V.; Atluri, V.; Jayant, R.D.; Yndart, A.; Kateb, B.; Pala, N.; Nair, M. Investigation of ac-magnetic field stimulated nanoelectroporation of magneto-electric nano-drug-carrier inside CNS cells. Sci. Rep. 2017, 7, srep45663.
  101. Qiu, Y.; Tong, S.; Zhang, L.; Sakurai, Y.; Myers, D.R.; Hong, L.; Lam, W.A.; Bao, G. Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions. Nat. Commun. 2017, 8, 15594.
  102. Wahajuddin; Arora, S. Superparamagnetic iron oxide nanoparticles: Magnetic nanoplatforms as drug carriers. Int. J. Nanomed. 2012, 7, 3445–3471.
  103. Raymond, A.D.; Diaz, P.; Chevelon, S.; Agudelo, M.; Yndart-Arias, A.; Ding, H.; Kaushik, A.; Jayant, R.D.; Nikkhah-Moshaie, R.; Roy, U.; et al. Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides. J. NeuroVirol. 2015, 22, 129–139.
  104. Ding, Y.; Qiao, A.; Fan, G.-H. Indirubin-3′-monoxime rescues spatial memory deficits and attenuates β-amyloid-associated neuropathology in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 2010, 39, 156–168.
  105. Sagar, V.; Pilakka-Kanthikeel, S.; Atluri, V.S.R.; Ding, H.; Arias, A.Y.; Jayant, R.D.; Kaushik, A.; Nair, M. Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate-Induced Neuropathogenesis and NeuroAIDS. J. Biomed. Nanotechnol. 2015, 11, 1722–1733.
  106. Pilakka-Kanthikeel, S.; Atluri, V.S.R.; Sagar, V.; Saxena, S.K.; Nair, M. Targeted brain derived neurotropic factors (BDNF) delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: An in-vitro study. PLoS ONE 2013, 8, e62241.
  107. Nair, M.P.N.; Saiyed, Z.M.; Gandhi, N.H. Magnetic nanoformulation of azidothymidine 5′-triphosphate for targeted delivery across the blood–brain barrier. Int. J. Nanomed. 2010, 5, 157–166.
  108. Jayant, R.D.; Atluri, V.S.; Agudelo, M.; Sagar, V.; Kaushik, A.; Nair, M. Sustained-release nanoART formulation for the treatment of neuroAIDS. Int. J. Nanomed. 2015, 10, 1077–1093.
  109. Nair, M.; Guduru, R.; Liang, P.; Hong, J.; Sagar, V.; Khizroev, S. Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers. Nat. Commun. 2013, 4, 1707.
  110. Kaushik, A.; Jayant, R.D.; Nikkhah-Moshaie, R.; Bhardwaj, V.; Roy, U.; Huang, Z.; Ruiz, A.; Yndart, A.; Atluri, V.; El-Hage, N.; et al. Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Sci. Rep. 2016, 6, 25309.
  111. Kaushik, A.K.; Rodriguez, J.; Rothen, D.; Bhardwaj, V.; Jayant, R.D.; Pattany, P.; Fuentes, B.; Chand, H.S.; Kolishetti, N.; El-Hage, N.; et al. MRI-Guided, Noninvasive Delivery of Magneto-Electric Drug Nanocarriers to the Brain in a Nonhuman Primate. ACS Appl. Bio Mater. 2019, 2, 4826–4836.
  112. Rodriguez, M.; Kaushik, A.; Lapierre, J.; Dever, S.M.; El-Hage, N.; Nair, M. Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood–Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in vitro. J. Neuroimmune Pharmacol. 2017, 12, 120–132.
  113. Kaushik, A.; Yndart, A.; Atluri, V.; Tiwari, S.; Tomitaka, A.; Gupta, P.; Jayant, R.D.; Alvarez-Carbonell, D.; Khalili, K.; Nair, M. Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection. Sci. Rep. 2019, 9, 3928.
  114. Yue, K.; Guduru, R.; Hong, J.; Liang, P.; Nair, M.; Khizroev, S. Magneto-electric nano-particles for non-invasive brain stimulation. PLoS ONE 2012, 7, e44040.
  115. Vakili-Ghartavol, R.; Momtazi-Borojeni, A.A.; Vakili-Ghartavol, Z.; Aiyelabegan, H.T.; Jaafari, M.R.; Rezayat, S.M.; Bidgoli, S.A. Toxicity assessment of superparamagnetic iron oxide nanoparticles in different tissues. Artif. Cells Nanomed. Biotechnol. 2020, 48, 443–451.
  116. Singh, N.; Jenkins, G.J.; Asadi, R.; Doak, S.H. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010, 1, 5358.
  117. Wei, H.; Hu, Y.; Wang, J.; Gao, X.; Qian, X.; Tang, M. Superparamagnetic Iron Oxide Nanoparticles: Cytotoxicity, Metabolism, and Cellular Behavior in Biomedicine Applications. Int. J. Nanomed. 2021, 16, 6097–6113.
  118. Xue, J.; Zhao, Z.; Zhang, L.; Xue, L.; Shen, S.; Wen, Y.; Wei, Z.; Wang, L.; Kong, L.; Sun, H.; et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat. Nanotechnol. 2017, 12, 692–700.
  119. Xu, J.; Wang, X.; Yin, H.; Cao, X.; Hu, Q.; Lv, W.; Xu, Q.; Gu, Z.; Xin, H. Sequentially Site-Specific Delivery of Thrombolytics and Neuroprotectant for Enhanced Treatment of Ischemic Stroke. ACS Nano 2019, 13, 8577–8588.
  120. Yuan, D.; Zhao, Y.; Banks, W.A.; Bullock, K.M.; Haney, M.; Batrakova, E.; Kabanov, A.V. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 2017, 142, 1–12.
  121. Qu, M.; Lin, Q.; Huang, L.; Fu, Y.; Wang, L.; He, S.; Fu, Y.; Yang, S.; Zhang, Z.; Zhang, L.; et al. Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease. J. Control. Release 2018, 287, 156–166.
  122. Turovsky, E.A.; Golovicheva, V.V.; Varlamova, E.G.; Danilina, T.I.; Goryunov, K.V.; Shevtsova, Y.A.; Pevzner, I.B.; Zorova, L.D.; Babenko, V.A.; Evtushenko, E.A.; et al. Mesenchymal stromal cell-derived extracellular vesicles afford neuroprotection by modulating PI3K/AKT pathway and calcium oscillations. Int. J. Biol. Sci. 2022, 18, 5345–5368.
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