scholarly journals Lipophilicity and Click Reactivity Determine the Performance of Bioorthogonal Tetrazine Tools in Pretargeted in Vivo Chemistry

2020 ◽  
Author(s):  
Johanna Stéen ◽  
Jesper Tranekjær Jørgensen ◽  
Denk Christoph ◽  
Umberto Maria Battisti ◽  
Kamilla Nørregaard ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Rational Design ◽  
Structural Parameters ◽  
Early Time ◽  
High Rate ◽  
Drug Conjugates ◽  
Compound Libraries ◽  
Drug Concentrations ◽  
The Impact

<p>The development of highly selective and fast biocompatible reactions for ligation and cleavage has paved the way for new diagnostic and therapeutic applications of <i>in vivo</i> chemistry. The concept of bioorthogonal pretargeting has attracted considerable interest, in particular for the targeted delivery of radionuclides and drugs. In nuclear medicine, pretargeting can provide increased target-to-background ratios at early time-points compared to traditional approaches. This reduces the radiation burden to healthy tissue and, depending on the selected radionuclide, enables better imaging contrast or higher therapeutic efficiency. Moreover, bioorthogonally triggered cleavage of pretargeted antibody-drug conjugates represents an emerging strategy to achieve controlled release and locally increased drug concentrations. The toolbox of bioorthogonal reactions has significantly expanded in the past decade, with the tetrazine ligation being the fastest and one of the most versatile <i>in vivo</i> chemistries. Progress in the field, however, relies heavily on the development and evaluation of (radio)labeled compounds, preventing the use of compound libraries for systematic studies. The rational design of tetrazine probes and triggers has thus been impeded by the limited understanding of the impact of structural parameters on the <i>in vivo</i> ligation performance. In this work, we describe the development of a pretargeted blocking assay that allows for the investigation of the <i>in vivo</i> fate of a structurally diverse library of 45 unlabeled tetrazines and their capability to reach and react with pretargeted <i>trans</i>-cyclooctene (TCO)-tagged antibodies in tumor-bearing mice. This study enabled us to assess the correlation of click reactivity and lipophilicity of tetrazines with their <i>in vivo</i> performance. In particular, high rate constants (>50,000 M<sup>-1</sup>s<sup>-1</sup>) for the reaction with TCO and low calculated log<i>D</i><sub>7.4</sub> values (below -3) of the tetrazine were identified as strong indicators for successful pretargeted <i>in vivo</i> click chemistry. Click-radiolabeling gave access to a set of selected <sup>18</sup>F-labeled tetrazines, including highly reactive scaffolds, which were used in pretargeted PET imaging studies to confirm the results from the blocking study. These insights thus enable the rational design of tetrazine probes for <i>in vivo</i> application and will thereby assist the clinical translation of bioorthogonal pretargeting.</p>

Lipophilicity and Click Reactivity Determine the Performance of Bioorthogonal Tetrazine Tools in Pretargeted in Vivo Chemistry

2020 ◽  
Author(s):  
Johanna Stéen ◽  
Jesper Tranekjær Jørgensen ◽  
Denk Christoph ◽  
Umberto Maria Battisti ◽  
Kamilla Nørregaard ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Rational Design ◽  
Structural Parameters ◽  
Early Time ◽  
High Rate ◽  
Drug Conjugates ◽  
Compound Libraries ◽  
Drug Concentrations ◽  
The Impact

<p>The development of highly selective and fast biocompatible reactions for ligation and cleavage has paved the way for new diagnostic and therapeutic applications of <i>in vivo</i> chemistry. The concept of bioorthogonal pretargeting has attracted considerable interest, in particular for the targeted delivery of radionuclides and drugs. In nuclear medicine, pretargeting can provide increased target-to-background ratios at early time-points compared to traditional approaches. This reduces the radiation burden to healthy tissue and, depending on the selected radionuclide, enables better imaging contrast or higher therapeutic efficiency. Moreover, bioorthogonally triggered cleavage of pretargeted antibody-drug conjugates represents an emerging strategy to achieve controlled release and locally increased drug concentrations. The toolbox of bioorthogonal reactions has significantly expanded in the past decade, with the tetrazine ligation being the fastest and one of the most versatile <i>in vivo</i> chemistries. Progress in the field, however, relies heavily on the development and evaluation of (radio)labeled compounds, preventing the use of compound libraries for systematic studies. The rational design of tetrazine probes and triggers has thus been impeded by the limited understanding of the impact of structural parameters on the <i>in vivo</i> ligation performance. In this work, we describe the development of a pretargeted blocking assay that allows for the investigation of the <i>in vivo</i> fate of a structurally diverse library of 45 unlabeled tetrazines and their capability to reach and react with pretargeted <i>trans</i>-cyclooctene (TCO)-tagged antibodies in tumor-bearing mice. This study enabled us to assess the correlation of click reactivity and lipophilicity of tetrazines with their <i>in vivo</i> performance. In particular, high rate constants (>50,000 M<sup>-1</sup>s<sup>-1</sup>) for the reaction with TCO and low calculated log<i>D</i><sub>7.4</sub> values (below -3) of the tetrazine were identified as strong indicators for successful pretargeted <i>in vivo</i> click chemistry. Click-radiolabeling gave access to a set of selected <sup>18</sup>F-labeled tetrazines, including highly reactive scaffolds, which were used in pretargeted PET imaging studies to confirm the results from the blocking study. These insights thus enable the rational design of tetrazine probes for <i>in vivo</i> application and will thereby assist the clinical translation of bioorthogonal pretargeting.</p>

scholarly journals Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 927
Author(s):  
Sebas D. Pronk ◽  
Erik Schooten ◽  
Jurgen Heinen ◽  
Esra Helfrich ◽  
Sabrina Oliveira ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Single Domain ◽  
Drug Conjugates ◽  
Intracellular Drug Delivery ◽  
Internalization Rate ◽  
Single Domain Antibodies ◽  
Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

scholarly journals The potential of microdialysis to estimate rifampicin concentrations in the lung of guinea pigs

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245922
Author(s):  
Faye Lanni ◽  
Neil Burton ◽  
Debbie Harris ◽  
Susan Fotheringham ◽  
Simon Clark ◽  
...  
Keyword(s):  
Drug Development ◽  
Guinea Pigs ◽  
Sampling Technique ◽  
Tissue Fluid ◽  
Experimental Conditions ◽  
Continuous Sampling ◽  
Drug Concentrations ◽  
The Impact

Optimised pre-clinical models are required for TB drug development to better predict the pharmacokinetics of anti-tuberculosis (anti-TB) drugs to shorten the time taken for novel drugs and combinations to be approved for clinical trial. Microdialysis can be used to measure unbound drug concentrations in awake freely moving animals in order to describe the pharmacokinetics of drugs in the organs as a continuous sampling technique. The aim of this work was to develop and optimise the microdialysis methodology in guinea pigs to better understand the pharmacokinetics of rifampicin in the lung. In vitro experiments were performed before progressing into in vivo studies because the recovery (concentration of the drug in the tissue fluid related to that in the collected dialysate) of rifampicin was dependent on a variety of experimental conditions. Mass spectrometry of the dialysate was used to determine the impact of flow rate, perfusion fluid and the molecular weight cut-off and membrane length of probes on the recovery of rifampicin at physiologically relevant concentrations. Following determination of probe efficiency and identification of a correlation between rifampicin concentrations in the lung and skeletal muscle, experiments were conducted to measure rifampicin in the sacrospinalis of guinea pigs using microdialysis. Lung concentrations of rifampicin were estimated from the rifampicin concentrations measured in the sacrospinalis. These studies suggest the potential usefulness of the microdialysis methodology to determine drug concentrations of selected anti-TB drugs to support new TB drug development.

scholarly journals Lipid Nanostructured Particles as Emerging Carriers for Targeted Delivery of Bioactive Molecules: Applications in Food and Biomedical Sciences (An Overview)

2020 ◽  
Vol 77 (1) ◽  
pp. 37
Author(s):  
Patricia MUNTEAN ◽  
Carmen SOCACIU ◽  
Mihai Adrian SOCACIU
Keyword(s):  
Targeted Delivery ◽  
Drug Carriers ◽  
Lipid Nanoparticles ◽  
Bioactive Molecules ◽  
Biomedical Sciences ◽  
Nanostructured Particles ◽  
Drug Conjugates ◽  
Carrier Systems

Lipid nanoparticles are getting a growing scientific and technological interest, worldwide. Either Solid Lipid Nanoparticles (SLNs), Nanostructured Lipid Carriers (NLCs), Lipid Drug Conjugates (LDCs) or Polymer-Lipid Nanoparticles (PLNs) have been produced and investigated last years, being reccomended as emerging carrier systems for many food and biomedical applications. An overview of the last publications, mainly since 2017 is presented, underlying the most important methods and techniques used for their preparation (e.g. high shear homogenization in hot and cold conditions, ultrasound assisted melt emulsification) as well techniques applied for measuring the size, calorimetric properties, zeta-potential, etc. Most relevant data related to the use of food-grade ingredients and designed lipid nanoparticles as delivery systems for organic and inorganic bioactive molecules in food or packaging’s are presented. The major reason for this trend in food science is the aim to overcome problems associated with the low bioavailability of many lipophilic bioactive compounds which are claimed to bring benefits to human health (carotenoid or anthocyanin pigments, sterols, vitamins). Finally, the recent applications of different formulas of lipid nanoparticles as drug carriers for in vitro experiments or for in vivo therapy (oral, parenteral or transdermal formulas) are presented.

scholarly journals Genetic signatures of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees

2018 ◽  
Author(s):  
Cody S. Nelson ◽  
Diana Vera Cruz ◽  
Melody Su ◽  
Guanhua Xie ◽  
Nathan Vandergrift ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Rational Design ◽  
Hcmv Infection ◽  
Vaccine Trial ◽  
The United States ◽  
Glycoprotein B ◽  
Viral Population ◽  
The Impact ◽  
Placebo Recipients

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide, and a frequent cause of hearing loss or debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child-bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating approximately 50% protection against HCMV infection of seronegative women in multiple phase 2 trials. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics of acutely-infected vaccinees and placebo recipients. First, there was reduced magnitude viral shedding in the saliva of gB vaccinees. Additionally, employing a panel of tests for genetic compartmentalization, we noted tissue-specific gB haplotypes in the majority of vaccinees though only in a single placebo recipient. Finally, we observed reduced acquisition of genetically-related gB1, gB2, and gB4 genotype “supergroup” HCMV variants among vaccine recipients, suggesting that the gB1 genotype vaccine construct may have elicited partial protection against HCMV viruses with antigenically-similar gB sequences. These findings indicate that gB immunization may have had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort.Author SummaryThough not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States - more than Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective preventative measures to inhibit congenital HCMV transmission following acute or chronic HCMV infection of a pregnant mother. However, the glycoprotein B (gB) vaccine is the most effective HCMV vaccine tried clinically to date. Here, we utilized high-throughput, next-generation sequencing of viral DNA isolated from patients enrolled in a gB vaccine trial, and identified several impacts that this vaccine had on the size, distribution, and composition of thein vivoviral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious and will inform future rational design of a vaccine to prevent congenital HCMV.

scholarly journals Modelling co-translational dimerisation for programmable nonlinearity in synthetic biology

2020 ◽  
Author(s):  
Ruud Stoof ◽  
Ángel Goñi-Moreno
Keyword(s):  
Nonlinear Dynamics ◽  
Biological Networks ◽  
Rational Design ◽  
Fine Tuning ◽  
Genetic Circuits ◽  
On Demand ◽  
Regulatory Circuits ◽  
Protein Dimers ◽  
The Impact

AbstractNonlinearity plays a fundamental role in the performance of both natural and synthetic biological networks. Key functional motifs in living microbial systems, such as the emergence of bistability or oscillations, rely on nonlinear molecular dynamics. Despite its core importance, the rational design of nonlinearity remains an unmet challenge. This is largely due to a lack of mathematical modelling that accounts for the mechanistic basics of nonlinearity. We introduce a model for gene regulatory circuits that explicitly simulates protein dimerization—a well-known source of nonlinear dynamics. Specifically, our approach focusses on modelling co-translational dimerization: the formation of protein dimers during—and not after—translation. This is in contrast to the prevailing assumption that dimer generation is only viable between freely diffusing monomers (i.e., post-translational dimerization). We provide a method for fine-tuning nonlinearity on demand by balancing the impact of co- versus post-translational dimerization. Furthermore, we suggest design rules, such as protein length or physical separation between genes, that may be used to adjust dimerization dynamics in-vivo. The design, build and test of genetic circuits with on-demand nonlinear dynamics will greatly improve the programmability of synthetic biological systems.

NKT Cells Are Potent Regulators of GVHD Following Adoptive Transfer in Allogeneic BMT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 353-353 ◽  
Author(s):  
Dennis B. Leveson-Gower ◽  
Janelle A. Olson ◽  
Jeanette Baker ◽  
Robert Zeiser ◽  
Andreas Beilhack ◽  
...  
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Early Time ◽  
Nkt Cells ◽  
Slight Reduction ◽  
Graft Vs Host Disease ◽  
Donor Type ◽  
And Migration ◽  
The Impact

Abstract NKT cells, which are CD1d reactive and express an invariant TCR, are thought to play an immunoregulatory role in suppressing dysfunctional immune reactions including graft vs. host disease (GVHD). Whether non-manipulated donor-type NKT can suppress GVHD following adoptive transfer has not been addressed, nor has the trafficking pattern of NKT in a hematopoetic transplantation (HCT) setting. To determine how effectively NKT proliferate and traffic in a HCT setting, 5.5x105 highly purified (>95%) NKT (DX5+TCRβ+CD4+) from luciferase positive (luc+) C57BL/6 (H-2b) mice were transferred into lethally irradiated Balb/c (H-2d) recipients along with 5x106 T-cell depleted bone marrow (TCD-BM) from wild-type C57BL/6 mice. Proliferation and migration of luc+NKT was monitored by bioluminescence imaging (BLI). By day 4 after transfer, a prominent signal was observed in the spleen and lymph node (LN) sites. Between days 7 and 10, the NKT migrated to skin, while still remaining present in high numbers in LNs, but decreasing to low levels in spleen. The total photons emitted per mouse reached a peak at approximately 25 days after transplantation, followed by a steady decline. The NKT expansion was more vigorous than that of luc+CD4+CD25+ regulatory T cells (Tregs), which also peak around day 25, but do not show extensive migration to skin. Expansion of NKT was far less than conventional (CD4+ and CD8+) T cells (Tcon), with approximately 10 times more photons/mouse being emitted from 5x105 luc+Tcon as from 5.5x105 NKT. The NKT did not cause GVHD where Tcon rapidly resulted in acute GVHD and animal mortality. To assess the impact of donor-type NKT on GVHD induction by Tcon, we co-transferred various doses of highly purified wt NKT at day 0 with 5x106 TCD-BM, followed by 5x105 luc+Tcon at day 2. Weight and survival of groups were monitored, as well as the proliferation of Tcon by BLI. In groups receiving only Tcon, 50% of the mice died within 2 weeks, and 90% died by day 80. Remarkably, if 2.5x104 sorted NKT were transferred, 100% of the mice survived past day 100. To achieve the same effect with Tregs, 2.5x105 Tregs were required. Mice treated with 2.5x104 NKT lost more weight at early time points than those receiving 2.5x105 Tregs, but both groups recovered from this weight loss and did not exhibit other signs of GVHD (hair loss, hunched back, diarrhea, etc). Interestingly, 2.5x104 NKT caused only a slight reduction in Tcon proliferation, whereas 2.5x105 Treg strongly reduced Tcon proliferation. Surprisingly, when the dose of NKT was increased to 5x104, survival was only 62%, and when increased to 1x105 cells, only 50% of mice survived past day 100. To determine how NKT reduce GVHD, we examined intracellular levels of various cytokines in Tcon with or without 2.5x104 NKT, following HCT. At 8 days after HCT, mice receiving NKT had reductions in the number of IL-17-positive cells (CD4: 2.6% to 0.84%; CD8: 2.5% to 0.66%), and TNFα+ cells (CD4: 45% to 27%; CD8 36% to 24%) in cells from LNs. By day 11, IL-17-positive cells had declined to undetectable levels and TNF levels between groups were equivalent. IFNg levels, which were high in both NKT treated and untreated groups at day 8 (85%–95%), decreased significantly in NKT treated mice by day 11 (CD4: 40%; CD8: 43%), but were still abundant in Tcon only mice (CD4: 78%; CD8: 80%). Together these data indicate that NKT cells persist in vivo upon adoptive transfer and suppress GVHD by decreasing the percentage of Tcon secreting pro-inflammatory cytokines.

scholarly journals Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 417
Author(s):  
Xinning Wang ◽  
Aditi Shirke ◽  
Ethan Walker ◽  
Rongcan Sun ◽  
Gopolakrishnan Ramamurthy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Maximum Tolerated Dose ◽  
In Vivo Studies ◽  
Castration Resistant Prostate Cancer ◽  
Drug Conjugates

Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.

High Prevalence and High Rate of Antibiotic Resistance of Mycoplasma genitalium Infections in Men who Have Sex with Men. A Sub-Study of the ANRS Ipergay PrEP Trial

2020 ◽  
Author(s):  
Béatrice Berçot ◽  
Isabelle Charreau ◽  
Rousseau Clotilde ◽  
Constance Delaugerre ◽  
Christian Chidiac ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycoplasma Genitalium ◽  
Urine Samples ◽  
High Rate ◽  
Post Exposure Prophylaxis ◽  
Open Label ◽  
Sex With Men ◽  
Incident Cases ◽  
The Impact

Abstract Background Mycoplasma genitalium (MG) is an emerging pathogen among men who have sex with men (MSM) with raising rates of antibiotic resistance. In this study, we assessed the prevalence and incidence of MG infection in MSM enrolled in the open-label phase of the ANRS IPERGAY trial with on demand TDF/FTC for HIV prevention and the impact of doxycycline post-exposure prophylaxis (PEP). Methods 210 subjects were tested at baseline and at 6 months by real-time PCR assays for MG detection in urine samples, oro-pharyngeal and anal swabs. Resistance to azithromycin (AZM), to fluoroquinolones (FQ) and to doxycycline were investigated in the French National Reference Centre of bacterial STI. Results The all-site prevalence of MG at baseline was 10.5% [6.3% in urine samples, 4.3% in anal swabs and 0.5% in throat swabs] and remained unchanged at 6 months whether or not PEP was used: 9.9% overall, 10.2% with PEP and 9.6% without. The overall rate of MG resistance (prevalent and incident cases) to AZM and FQ was 67.6% and 9.1%, respectively, with no difference between arms. An in vivo mutation of the MG 16S rRNA which could be associated with tetracycline resistance was observed in 12.5% of specimens tested. Conclusions The prevalence of MG infection among MSM on PrEP was high and its incidence was not decreased by doxycycline prophylaxis with a similar high rate of AZM- and FQ-resistance, raising challenging issues for the treatment of this STI and supporting current recommendations to avoid testing or treatment of asymptomatic MG infection.

scholarly journals Advances in Non-Animal Testing Approaches towards Accelerated Clinical Translation of Novel Nanotheranostic Therapeutics for Central Nervous System Disorders

Nanomaterials ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 2632
Author(s):  
Mark J. Lynch ◽  
Oliviero L. Gobbo
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Rational Design ◽  
In Vitro Models ◽  
Clinical Translation ◽  
Clinical Testing ◽  
Cns Disorders ◽  
Novel Drug

Nanotheranostics constitute a novel drug delivery system approach to improving systemic, brain-targeted delivery of diagnostic imaging agents and pharmacological moieties in one rational carrier platform. While there have been notable successes in this field, currently, the clinical translation of such delivery systems for the treatment of neurological disorders has been limited by the inadequacy of correlating in vitro and in vivo data on blood–brain barrier (BBB) permeation and biocompatibility of nanomaterials. This review aims to identify the most contemporary non-invasive approaches for BBB crossing using nanotheranostics as a novel drug delivery strategy and current non-animal-based models for assessing the safety and efficiency of such formulations. This review will also address current and future directions of select in vitro models for reducing the cumbersome and laborious mandate for testing exclusively in animals. It is hoped these non-animal-based modelling approaches will facilitate researchers in optimising promising multifunctional nanocarriers with a view to accelerating clinical testing and authorisation applications. By rational design and appropriate selection of characterised and validated models, ranging from monolayer cell cultures to organ-on-chip microfluidics, promising nanotheranostic particles with modular and rational design can be screened in high-throughput models with robust predictive power. Thus, this article serves to highlight abbreviated research and development possibilities with clinical translational relevance for developing novel nanomaterial-based neuropharmaceuticals for therapy in CNS disorders. By generating predictive data for prospective nanomedicines using validated in vitro models for supporting clinical applications in lieu of requiring extensive use of in vivo animal models that have notable limitations, it is hoped that there will be a burgeoning in the nanotherapy of CNS disorders by virtue of accelerated lead identification through screening, optimisation through rational design for brain-targeted delivery across the BBB and clinical testing and approval using fewer animals. Additionally, by using models with tissue of human origin, reproducible therapeutically relevant nanomedicine delivery and individualised therapy can be realised.

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