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

Abstract

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.

The Advances in Glioblastoma On-a-Chip for Therapy Approaches

“…The increased complexity in the elaboration of the devices verified in this review (18.2% level IV [ 41 , 44 , 46 , 56 ], 40.9% level III [ 45 , 47 , 48 , 50 , 51 , 53 , 54 , 55 , 57 , 59 , 60 ], and 36.4% level II [ 39 , 40 , 43 , 49 , 58 ]) has reflected the diversity of components present in the real tumor microenvironment, as well as the responses obtained from the interaction of the different systems, cells and ECM, as described in the study by Jo et al [ 50 ] that observed chemoresistance regarding the use of Matrigel in the treatment with DOX, among other aspects. In this sense, the literature has proven that the responses of organ-on-a-chip studies have been increasingly closer to in vivo studies than the results obtained in in vitro [ 86 , 87 ], and represents an excellent platform for validation of therapeutic processes for glioblastoma tumors.…”

Dendritic cell vaccines improve the glioma microenvironment: Influence, challenges, and future directions

“…Mature DC cultured in vitro can induce other immune cells to migrate to the tumor site by chemokines, thus improving the immune microenvironment of patients. 92 The mRNA levels of both CCL10 and TLR3 were significantly upregulated after the first and fourth DC vaccination, and CCL10 could guide CD8+ T cells into brain tumor sites, 93 thus improving the inhibitory immune microenvironment in glioma patients. 94 Hirokazu Ogino et al pretreated DCs with poly‐ICLC and found that in addition to upregulating cytokines such as IFN‐γ, TNF‐α, and IL‐10, 95 the migration of effector memory CD8+ T cells in the TME may be mediated through the CXCL10/CXCR3 axis, 96 which showed the activating DCs can effectively improve the migration of other immune cells and improve the tumor microenvironment by regionalization factors.…”

“…Mature DC cultured in vitro can induce other immune cells to migrate to the tumor site by chemokines, thus improving the immune microenvironment of patients 92 . The mRNA levels of both CCL10 and TLR3 were significantly upregulated after the first and fourth DC vaccination, and CCL10 could guide CD8+ T cells into brain tumor sites, 93 thus improving the inhibitory immune microenvironment in glioma patients 94 .…”

Towards Novel Biomimetic In Vitro Models of the Blood–Brain Barrier for Drug Permeability Evaluation

“…In this line, smart drug delivery systems might offer several advantages in comparison to traditional drug delivery systems. Further details are included in the extensive review from Lynch and Gobbo, in which the advantages of nanoparticle-based smart drug delivery systems crossing through the BBB versus traditional drug delivery systems are deeply discussed [25]. Briefly, ligand decoration is crucial to ensure an optimum transcellular transport of the nanomedicine, especially to promote receptor-mediated transcytosis, which is the most used method for intracerebral delivery.…”

“…However, Lynch and Gobbo also pointed out the issues for clinic translation, mainly related to the lack of realistic models [25]. Intracerebral drug delivery then faces two great challenges.…”