Nanomedicine-based immunotherapy for central nervous system disorders

Abstract

Central nervous system (CNS) disorders represent a broad spectrum of brain ailments with short- and long-term disabilities, and nanomedicine-based approaches provide a new therapeutic approach to treating CNS disorders. A variety of potential drugs have been discovered to treat several neuronal disorders; however, their therapeutic success can be limited by the presence of the blood-brain barrier (BBB). Furthermore, unique immune functions within the CNS provide novel target mechanisms for the amelioration of CNS diseases. Recently, various therapeutic approaches have been applied to fight brain-related disorders, with moderate outcomes. Among the various therapeutic strategies, nanomedicine-based immunotherapeutic systems represent a new era that can deliver useful cargo with promising pharmacokinetics. These approaches exploit the molecular and cellular targeting of CNS disorders for enhanced safety, efficacy, and specificity. In this review, we focus on the efficacy of nanomedicines that utilize immunotherapy to combat CNS disorders. Furthermore, we detailed summarize nanomedicine-based pathways for CNS ailments that aim to deliver drugs across the BBB by mimicking innate immune actions. Overview of how nanomedicines can utilize multiple immunotherapy pathways to combat CNS disorders.

Keywords: blood–brain barrier; central nervous system disorders; immunotherapy; nanomedicine.

Overview of how nanomedicines can utilize multiple immunotherapy pathways to combat CNS disorders.

Fig. 1. Representation of the common in vitro BBB cellular models for CNS diseases.

Reproduced with permission from [79]. Copyright 2015 Wolters Kluwer—Medknow

Fig. 2. Optimal design of nanoparticle-based delivery of drugs, cargoes/or adjuvants, and immunotherapy of glioblastoma.

Diverse types of nanoscale materials can serve as vehicles for targeted delivery of tumor-cytotoxic nanomedicines

Fig. 3. Nanomedicines based immunotherapies of glioma tumors.

a Schematic illustration of the hybrid ‘clusterbomb’ nanovaccines MPSDP–ZnO/Ag, which activates the cytotoxicity of regulatory T cells (Tregs) in the brain with F98npEGFRvIII-bearing rats. Reproduced with permission from [106]. Copyright 2019 Royal Society of Chemistry. b The schematic diagram of the synthesis and characterization of NICs. c The ELISA method used for validation of concurrent conjugation and activity of anti-msTfR and anti-CTLA-4/anti-PD-1 expression within a single platform and combined P/anti-CTLA-4 d and P/anti-PD-1, respectively. d The anticipated mechanism of local brain immune activation by NIC therapy, which utilizes synergistic treatment with anti-CTLA-4 and anti-PD-1 mAbs when the nanoimmune drug crosses the BBB. 1, 2, and 3 are different pathways and immune checkpoints that are activated or suppressed via NIC. Reproduced with permission from [111]. Copyright 2019 Nature Publishing Group

Fig. 4. The immune-mediated antiglioma mechanism utilized in docetaxel-loaded CpG-sHDL (high-density lipoprotein) nanodiscs, CpG oligodeoxynucleotide expressed by TRL9 ligand of immune cells.

a DTX-sHDL-CpG is formulated by incubating lipid-DTX (docetaxel) with CpG and preformed sHDL. b Intratumoral delivery of DTX-sHDL-CpG nanodiscs in combination with radiation results in Chemo-immuno-antiglioma activity. HDL-mimicking nanodiscs deliver the DTX payload to tumor cells in the TME, to suppress their microtubule depolymerization, resulting in mitotic cell cycle arrest in the G2/M phase (cell differentiation phases) and tumor cell death. In addition, radiation induces double-stranded DNA breaks, also leading to tumor cell death. Dying tumor cells express regulatory T cells (CRT) on their surface and are engulfed by antigen-presenting DCs and macrophages. Reprinted with permission from [125]. Copyright 2019, American Chemical Society

Fig. 5. Synthetic diagram of photo-immunoconjugate nanoparticles (PIC-NPs).

a The illustration of PIC synthesis by conjugation of BPD derivative photosensitizers to PEGylated cetuximab via carbodiimide crosslinker chemistry. b showing the various stoichiometry of BPD reacted with cetuximab species. c Transmission electron microscopy (TEM) image of poly (ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) polymeric nanoparticles prepared via nanoprecipitation method. Scale bar 100 nm. d Schematic representation of PIC-NP synthesis via copper-free click chemistry. Azide-containing FKR560 dye-loaded PLGA nanoparticles were reacted with the dibenzocyclooctyne (DBCO)-containing PICs to form PIC-NPs. e Covalent conjugation of PICs onto 80 nm PEG-PLGA NPs resulted in the formation of monodispersed PIC-NPs around 100 nm in diameter. Adapted with permission from [140]. Copyright 2018 WILEY‐VCH Verlag GmbH & Co

Fig. 6

a Schematic route for the delivery of gene combination therapy using siRNA loaded nanoparticles for brain tumor treatment. b The chemical structure of the DSPE-PEG (2000)-DBCO, Esterquat, and iRGD peptide, and the construction of the nanoparticles SLN, f(SLN), f(SLN)–iRGD, and f(SLN)–iRGD:siRNA. Adapted with permission from [156]. Copyright 2019 American Chemical Society

Fig. 7

Clearance mechanisms of amyloid-β based on immunotherapeutic approaches for AD pathology

Fig. 8. The immune-modulating effect of a zwitterionic poly(carboxybetaine) (PCB)-based nanoparticles (Man-PCBPB/ZnO/fingolimod/siSTAT3 NPs: MCPZFS) for AD therapy.

a Structural composition and preparation of the MCPZFS for AD therapy. b The mechanism of MCPZFS BBB permeability and binding with Aβ for endocytosed into microglia cells. Reproduced with permission from [185]. Copyright 2019, WILEY‐VCH Verlag GmbH & Co

Fig. 9. GQDs as nanomedicine for α-synuclein fibrillization and their disaggregation process.

a Schematic representation of α-synuclein fibrillization (5 mg/mL α-synuclein monomers) and disaggregation (5 mg/mL α-synuclein fibrils) before and after the addition of GQDs (5 mg/mL). b Transmission electron microscopy images show α-synuclein fibrillization before and after the addition of GQDs. c In vitro quantification of the effect of GQDs on α-synuclein preformed fibrils (PFF)-induced neuronal death via phosphorylated α-synuclein (p-α-synuclein) immunofluorescence. d Illustration of the microfluidic device component for the transmission of pathologic α-synuclein. e, f Kinetics measurements of α-synuclein fibrils after incubation with GQDs via thioflavin T (ThT)-based fluorescence and turbidity assays, respectively. g, h Kinetics measurement and turbidity assays for α-synuclein fibrillization via ThT-based fluorescence, respectively. Reproduced with permission from [205]. Copyright 2018 Nature Publishing group