Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives
Abstract
1. Introduction
2. Local CNS Administration Routes and Challenges
2.1. ICV
2.2. CED
2.3. IT
2.4. Others
3. Formulation Strategies to Improve CNS Protein/Peptide Delivery
3.1. Peptide/Protein Functionalization Strategies
3.2. Long-Acting Formulations
3.3. Nanotechnology-Based Delivery Systems
3.4. Extracellular Vesicles
3.5. Live-Cell Therapy
4. Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Pros | Cons | Clinical Applications | |
---|---|---|---|
ICV | Direct introduction of nearly 100% therapeutics into the CSF in the lateral ventricle with minimal drug-protein bounding. | Low drug distribution in the brain parenchyma that is away from the injection site; Bulk flow of CSF may result in fast clearance and systemic exposure; Complications associated with ICV device implantation. | Brineura [16]; tripeptidyl peptidase 1 (Phase I/II) [17,18]; idursulfase-β (Phase I/II) [19]; telbermin (Phase I) [20] |
CED | Improved drug distribution in the brain parenchyma; Topographically more restricted, thus less complications compared to ICV. | Inefficient diffusion in the parenchyma for some macromolecules; Complications from the invasiveness of the CED. | Omburtamab (Phase I) [21,22] |
IT | Direct injection of nearly 100% therapeutics into the CSF in the spinal subarachnoid space with long half-life in the CSF due to minimal drug-protein bounding and metabolism; Less invasive compared to ICV and CED | Less macromolecule distribution in the parenchyma compared to ICV and CED; Potential complications from IT device implantation. | Recombinant human arylsulfatase A(Phase I/II) [23] |
IN | Noninvasive | Potential systemic exposure; Device design is critical. | Insulin & insulin detemir (Phase II) [6]; neuropeptide Y (Phase I) [7] |
Disease Model | Formulation | Cargo Therapeutic | Carrier Material | Release Duration | Ref. |
---|---|---|---|---|---|
GBM (GL261 mouse model) | Hydrogel | CXCL-10 | Self-assembled oligopeptide | >12 days | [73] |
Spinal cord injury (Rat model) | Hydrogel | basic fibroblast growth factor (bFGF) or FGF2 | Heparin-modified poloxamer and lyophilized acellular spinal cord | >7 days | [74,75] |
Nanoparticle (NP)-hydrogel composite | neurotrophin-3 (NT-3) + antibody 11c7 (anti-NogoA) | Hyaluronan-methylcellulose (HAMC) and poly(lactic-co-glycolic acid) (PLGA) | NT-3: >58 days; anti-NogoA: >10 days | [76] | |
Hydrogel | NT-3 | Heparin-contained collagen | >90 days | [77] | |
NP-hydrogel composite | chondroitinase ABC (ChABC) + stromal cell-derived factor 1α (SDF) | SH3 binding peptide-modified methylcellulose and PLGA | ChABC: >7 days; SDF: >14 days | [78] | |
Liposome-hydrogel composite | brain-derived neurotrophic factor (BDNF) + acidic FGF (aFGF) | Heparin-modified poloxamer and scar-targeted tetrapeptide-modified liposomes | BDNF/aFGF: >21 days | [79] | |
NP-hydrogel composite | BDNF | Agarose + polysaccharide polyelectrolyte complexes | >17 days | [80] | |
Hydrogel | Anti-inflammatory peptide KAFAK + BDNF | HAMC | KAFAK/BDNF: >4 days (only ~50% of payloads released) | [81] |
Disease Model | Formulation | Cargo Therapeutic | Administration | Ref. |
---|---|---|---|---|
Spinal cord injury (Rat model) | PLGA NP | NT-3 | IT | [88] |
Brain tumor (Mouse model) | Lipidoid-telodendrimer binary hybrid NP | DT390 | CED | [89] |
AD (Rat model) | Lectin-modified PEG-PLGA NP | bFGF | IN | [90] |
PD (Rat model) | Phospholipid-based gelatin NP | bFGF | IN | [91] |
Mouse model | Chitosan coated nanostructured lipid carriers | human IGF-I (hIGF-I) | IN | [92] |
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Yue, W.; Shen, J. Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives. Pharmaceuticals 2023, 16, 810. https://doi.org/10.3390/ph16060810
Yue W, Shen J. Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives. Pharmaceuticals. 2023; 16(6):810. https://doi.org/10.3390/ph16060810
Chicago/Turabian StyleYue, Weizhou, and Jie Shen. 2023. "Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives" Pharmaceuticals 16, no. 6: 810. https://doi.org/10.3390/ph16060810
APA StyleYue, W., & Shen, J. (2023). Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives. Pharmaceuticals, 16(6), 810. https://doi.org/10.3390/ph16060810