Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease
Abstract
:1. Introduction
2. Alzheimer’s Disease—Pathogenesis and Therapeutical Routes
3. Dendrimers—A Multivalent and Multifunctional Nanocarrier
4. Dendrimers as Anti-Amyloidogenic Agents
4.1. Dendrimer/Peptide Ratio
4.2. Functional Surface Groups
4.3. Generation
4.4. Topology
5. Dendrimers as Anti-Tau Agents and Inhibitors of Acetylcholinesterase Activity
6. Dendritic Structures as Anti-Inflammatory Agents
6.1. Functional Surface Groups
6.2. Generation/Size and Multivalency
6.3. Internal Structure
7. Dendrimers as Antioxidants and Chelators
8. Dendrimers as Nanocarriers
9. The Other Side of Dendrimers—Caveats and Challenges
10. Concluding Remarks and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Dendrimer (No. Terminal Groups (1)) | Terminal Group (Charge) | Dendrimer/Peptide Ratio | Effect on Fibrillation (to Peptide Alone) | Morphology and Secondary Structure of Fibrils | Disaggregation Ability? | Attenuation of Aβ Cytotoxicity? (Cell Type) | Refs. |
---|---|---|---|---|---|---|---|
G3 PAMAM (32) | -NH2 (+) | 0.0002 | ↑ elongation rate; | Clumps | Yes * | Yes (SH-SY5Y) | [19,104,124] |
0.002 | ↓ elongation rate and fibril amount (~30%) | ||||||
0.02 | ↓ elongation rate and fibril amount (~ 50%) | ||||||
0.10 | Complete inhibition of aggregation | ||||||
G4 PAMAM (64) | -NH2 (+) | 0.0002 | ↑ elongation rate; | Yes * | Yes (SH-SY5Y) | [104,124] | |
0.002 | ↓ fibril amount (~30%) | ||||||
0.02 | ↓ elongation rate and fibril amount (~65%) | ||||||
G5 PAMAM (128) | -NH2 (+) | 0.0002 | ↑ elongation rate | Amorphous aggregates | Yes * | [104,124] | |
0.002 | ↓ elongation rate and fibril amount (25%) | ||||||
0.02 | Complete inhibition of aggregation | ||||||
G3 CPD (48) | -NHEt (+) | 0.0002 | ↑ elongation rate and fibril amount (~60%) | Long fibrils. Accelerated the conformational transition to β-sheet | Yes (N2a) | [21] | |
0.0002 | No effect | Accelerated the conformational transition to β-sheet | |||||
0.02–0.2 | Complete inhibition of aggregation | No fibrils. Inhibition on transition to β-sheet. | |||||
G4 CPD (96) | -NHEt (+) | 0.0002 | ↑ elongation rate and fibril amount (~60%) | Long fibrils. Accelerated the conformational transition to β-sheet | Yes | Yes (N2a) | [21] |
0.0002 | ↑ elongation rate and fibril amount (~20%) | ||||||
0.02–0.2 | Complete inhibition of aggregation | No fibrils. Inhibition on transition to β-sheet. | |||||
G3 PPI (16) | -NH2 (+) | 0.02 | ↑ elongation rate; ↓ fibril amount (↓ 12%) | Yes * | [22] | ||
0.03 | ↑ elongation rate; ↓ fibril amount (↓ 56%) | ||||||
0.04 | ↓ fibril amount (↓ 56%) | ||||||
0.08 | Complete inhibition of aggregation | ||||||
G4 mPPI (32 (64)) | Maltose (0) | 0.1 | ↑ elongation rate | Clumped fibrils | Yes * | Yes (PC12/SH-SY5Y) | [20,118,122] |
1 | ↑ elongation rate | ||||||
5 | ↓ elongation rate and fibril amount (↓ ~50%) | ||||||
10 | ↓ elongation rate and fibril amount (↓ ~80%) | ||||||
G4 m-IIIPPI OS (32 (64)) | -NH (36%)/-NH2 (28%)/Maltotriose (36%) (+) | 0.01 | Complete inhibition of aggregation | Granular aggregates | No | [118] | |
G4 mPPI OS (32 (64)) | -NH (37.5%)/ -NH2 (25%)/Maltose (37.5%) (+) | 0.01 | ↑ nucleation rate, elongation rate and fibril amount (↑ 100%) | Fibrillar. No oligomers | Yes (SH-SY5Y) | [118] | |
>0.01 | Complete inhibition of aggregation | ||||||
G5 mPPI (64 (128)) | -NH (10%)/Maltose (90%) (0) | 0.005 | ↑ nucleation and elongation rate | Fibrillar. No oligomers | Yes (PC12/SH-SY5Y) | [20,118] | |
0.1–10 | Complete inhibition of aggregation | Amorphous aggregates | |||||
G5 mPPI (64 (128)) | Maltose (0) | 0.002 | ↑ elongation rate and fibril amount (↑ 120%) | Acceleration of the conformational transition to β-sheet | [119] | ||
0.02 | ↑ elongation rate and fibril amount (↑ 100%) | ||||||
0.2 | Complete inhibition of aggregation | Inhibition of conformational transition to β-sheet. | |||||
G5 m-IIIPPI (64 (128)) | -NH (6%)/Maltotriose (94%) (0) | 0.002 | ↑ elongation rate and fibril amount (↑ 100%) | Acceleration of the conformational transition to β-sheet | [119] | ||
0.02 | ↑ fibril amount (↑ ~20%) | ||||||
0.2 | Complete inhibition of aggregation | Inhibition of conformational transition to β-sheet. | |||||
G5 mPPI SO3 (64 (128)) | Maltose/ -O-SO3− (0.76 equivalent of OH units) (−) | 0.0002 | ↓ fibril amount (↓ ~25%) | Yes (mHippoE-18) | [120] | ||
0.002 | ↓ fibril amount (↓ ~45%) | ||||||
0.02 | ↓ fibril amount (↓ ~45%) | Slows down the conformational transition to β-sheet | |||||
G4HisMal (64 (128)) | -NH (32%)/Maltose (48%)/Histine (20%) (+) | 0.10 | ↓ elongation rate and fibril amount (↓ ~65%) | No oligomers. Mesh like fibrils | Yes (SH−SY5Y) | [26] | |
1 | ↓ elongation rate and fibril amount (↓ ~75%) | No oligomers. More irregular aggregates | |||||
GATG-Mor (27) | Morpholine (0) | 0.0002 | No effect | Yes (B14) | [110] | ||
0.002 | ↑ fibril amount (↑ 25%) | ||||||
0.02 | ↑ elongation and fibril amount (↑ 116%) | Long fibrils; ↑ fibrils; Faster conformational transition to β-sheet | |||||
2G0-GaOH (2) | Gallic acid (-OH) (0) | 0.5 | Complete inhibition of aggregation | Yes | Yes (SH-SY5Y) | [111] | |
1 | Complete inhibition of aggregation. ↓ final amount of ThT+ aggregates in cell culture (~50%). | ↓ of non-fibrillar structures (~20%); ↓ Elongated fibrils. ↑ unstructured aggregates (condensed and less organized) and/or shorter fibrils | |||||
2 | Complete inhibition of aggregation | ||||||
2G1-Ga-OH (6) | Gallic acid (-OH) (0) | 0.5 | Complete inhibition of aggregation | Yes | Yes (SH-SY5Y) | [111] | |
1 | Complete inhibition of aggregation. ↓ final amount of ThT+ aggregates in cell culture (~60%). | ↓ of non-fibrillar structures (~43%); ↓ small aggregates (~10%); ↓ Elongated fibrils; ↑ unstructured aggregates (condensed and less organized) and/or shorter fibrils | |||||
2 | Complete inhibition of aggregation | ||||||
3G1-Ga-OH (9) | Gallic acid (-OH) (0) | 0.5 | Complete inhibition of aggregation | Yes | Yes (SH-SY5Y) | [111] | |
1 | Complete inhibition of aggregation. ↓ the final amount of ThT+ aggregates in cell culture (~40%). | ↓ of non-fibrillar structures (~32%); ↓ Elongated fibrils; ↑ unstructured aggregates (condensed and less organized) and/or shorter fibrils | |||||
2 | Complete inhibition of aggregation | ||||||
G3 Lysine dendrimer (8) | (CH2)4NH3+(+) | 0.02 | ↑ nucleation rate, elongation rate and fibril amount (↑ ~20%) | Yes (SH-SY5Y) | [125] | ||
0.1 | ↑ nucleation rate and elongation rate | ||||||
G5 Lysine dendrimer (26) | (CH2)4NH3+ (+) | 0.02 | ↓ nucleation rate, elongation rate and fibril amount (↓ ~100%) | [125] | |||
0.1 | ↑ fibril amount (↑ ~50%) | ||||||
G3/G4 PAMAM-COOH (32/64) | -COOH (−) | 0.1–25 | No effect | Fibrillar. No change in the secondary structure of the peptides | [126] | ||
G5 PAMAM-COOH (128) | -COOH (−) | 0.1–10 | No effect | Fibrillar. No change in the secondary structure of the peptides | No (SH-SY5Y) | [107] | |
25 | ↓ fibril amount (20%) | ||||||
G6 PAMAM-COOH (256) | -COOH (−) | 0.1–25 | No effect | Fibrillar. No change in the secondary structure of the peptides | [126] | ||
G3 PAMP (32) | -COOH/Phenyl groups (28.8%) (−) | 0.01 | No effect | Fibrillar. No change in the secondary structure of the peptides | [126] | ||
0.1–1 | ↑ elongation rate and fibril amount (up to 30%) | ||||||
G4 PAMP (64) | -COOH/ Phenyl groups (28.2%) (−) | 0.01–0.5 | ↑ elongation rate and fibril amount (up to 30%) | Fibrillar. No change in the secondary structure of the peptides | [126] | ||
1 | ↑ elongation rate | ||||||
G5 PAMP (128) | -COOH/ Phenyl groups (7.2%) (−) | 0.01 | ↓ fibril amount (↓ ~10%) | Fibrillar. No change in the secondary structure of the peptides | Yes (SH-SY5Y) | [107] | |
0.1 | ↓ fibril amount (↓ ~15%) | ||||||
0.5 | ↓ fibril amount (↓ ~20%) | ||||||
1 | ↓ elongation rate and fibril amount (↓ ~28%) | ||||||
-COOH/ Phenyl groups (21.2%) (−) | 0.01 | ↓ fibril amount (↓ ~15%) | Fibrillar. No change in the secondary structure of the peptides | Yes (SH-SY5Y) | [107] | ||
0.1 | ↓ fibril amount (↓ ~20%) | ||||||
0.5 | ↓ fibril amount (↓ ~30%) | ||||||
1 | ↓ elongation rate and fibril amount (↓ ~38%) | ||||||
-COOH/ Phenyl groups (30.5%) (−) | 0.01 | ↓ fibril amount (↓ ~25%) | Irregular aggregates. Inhibition on the conformational transition to β-sheet at the equimolar ratio of peptide/dendrimer | Yes (SH-SY5Y) | [107,126] | ||
0.1 | ↓ fibril amount (↓ ~35%) | ||||||
0.5 | ↓ fibril amount (↓ ~40%) | ||||||
1 | ↓ elongation rate and fibril amount (↓ ~70%) | ||||||
-COOH/ Phenyl groups (42.3%) (−) | 0.01 | ↓ fibril amount (↓ ~25%) | Irregular aggregates. Inhibition on the conformational transition to β-sheet at the equimolar ratio of peptide/dendrimer | Yes (SH-SY5Y) | [107] | ||
0.1 | ↓ fibril amount (↓ ~40%) | ||||||
0.5 | ↓ fibril amount (↓ ~50%) | ||||||
1 | ↓ elongation rate and fibril amount (↓ ~70%) | ||||||
G6 PAMP (256) | -COOH/ Phenyl groups (28.8%) (−) | 0.01–1 | ↓ elongation rate and fibril amount in a concentration-dependent manner. At peptide/dendrimer ratio 1:0.5 ↓ fibril amount by 70% | Irregular aggregates. Inhibition on the conformational transition to β-sheet at the equimolar ratio of peptide/dendrimer | [126] | ||
G5 PAMP-OH (128) | -OH/Phenyl groups (28.8%) (+) | 0.1–1 | No effect | No effect at different peptide/dendrimer ratios | [107] | ||
APD (8) | -SO3− (50%)/CH2CH2CH3 (50%) (−) | 0.125 | ↓ elongation rate and fibril amount to 66.5% | Fibrillar structures | Yes | [127] | |
0.2 | ↓ elongation rate and fibril amount to ~60% | Fibrillar structures | |||||
1 | ↓ elongation rate and fibril amount to ~10% | Amorphous aggregates and fibrils | Yes (primary murine neuronal cells) | ||||
0.75 | ↓ elongation rate and fibril amount to 52% | Amorphous aggregates and few fibrils | |||||
4 | Complete inhibition of fibrillation | Amorphous aggregates; Inhibition of transition to β-sheet | Yes (primary murine neuronal cells) | ||||
SA-D (32) | -SO3− (50%)/CH2CH2CH3 (50%) (−) | 0.125 | ↓ elongation rate and fibril amount to 66.3% | Amorphous aggregates and fibrils | Yes | [127] | |
0.333333333 | ↓ elongation rate and fibril amount to 50.4% | Amorphous aggregates and few fibrils | |||||
0.5–1 | Complete inhibition of fibrillation | Amorphous aggregates | Yes (primary murine neuronal cells) |
Dendrimer (No. Terminal Groups) | Terminal Group (Charge) | Type of Assay | Biodistribution & Cellular Uptake | Effect on Inflammation | Refs. |
---|---|---|---|---|---|
G4 PAMAM (64) | -NH2 (+) | in vivo/ in vitro | Biodistribution: CP newborn rabbit model • i.p.: only found at the injection site. • i.v.: only present inside blood vessels Cellular uptake: BV2 microglial cells • Dendrimer uptake: 0.093 ± 0.01 pg/cell (resting state) & 0.517 ± 0.01 pg/cell (LPS-activated) • 2-fold lower uptake than neutral G4 PAMAM-OH | In vivo Carrageenan-induced paw edema in Rats • 35.50 ± 1.64% inhibitory activity of paw edema at 16 mg/kg dose, 4 h post-administration Cotton Pellet Test in Rats • Exhibited higher inflammatory inhibition than indomethacin alone Adjuvant-induced Arthritis in Rats • Exhibited higher inflammatory activity than indomethacin alone (25 ± 2.1 vs. 18 ± 0.7, p < 0.05) In vitro • Exhibited COX-1 and COX-2 inhibition and ~50% reduction of the NO production on LPS-activated rat peritoneal macrophages | [160,175,176] |
-OH (0) | in vivo/ in vitro | Biodistribution: CP newborn rabbit model • i.p.: found within the cells several millimeters. • i.v.: Co-localization with activated microglia in CP kits (but not in healthy age-matched) 4 h post-injection. Extent of dendrimer uptake correlated with the extent of disease Cellular uptake: BV2 microglial cells • Maximal Dendrimer uptake (resting): 0.201 ± 0.02 (pg/cell) • 4.05-fold increase in maximal dendrimer uptake by LPS stimulation (0.814 ± 0.08 pg/cell) | In vivo Carrageenan-induced paw edema in Rats • 31.22 ± 1.58% inhibitory activity towards paw edema at 16 mg/kg dose, 4 h post-administration In vitro • COX-2 inhibition (not COX-1) and ~50% reduction of NO production on LPS-activated rat peritoneal macrophages | [83,160,175,176,177] | |
G3.5 PAMAM (64) | -COOH (−) | in vivo | Biodistribution: CP newborn rabbit model (i.v.) • i.v.: co-localized with microglial cells 24h post-injection Cellular uptake: BV2 microglial cells • Maximal Dendrimer uptake (resting): 0.234 ± 0.01 pg/cell • 1.72-fold increase in maximal dendrimer uptake by LPS stimulation (0.404 ± 0.01 pg/cell) | In vivo Carrageenan-induced paw edema in Rats • 11.00 ± 1.60% inhibitory activity towards paw edema at 16 mg/kg dose, 4 h post-administration In vitro • ~43% reduction of the NO production on LPS-activated rat peritoneal macrophages. Inhibitory activity was significantly lower than G4 PAMAM-NH2 and G4 PAMAM-OH (p < 0.05) • Did not exhibit COX inhibition on LPS-activated rat peritoneal macrophages | [160,175,176] |
-COOH/Glucosamine (14%) (−) | in vitro | in vitro • Significant reduction in the release of the pro-inflammatory chemokines (MIP-1α, MIP-1β, IL-8, TNF-α, IL-1β and IL-6) in LPS-activated human PDMC • Significant reduction in the release of the pro-inflammatory chemokines (MIP-1β and TNF-α in LPS-activated human DC and MDM • Inhibited lymphocyte proliferation in the mixed leukocyte reaction and prevent INF-γ production | [159] | ||
G6 PAMAM (256) | -OH (0) | in vivo/ in vitro | Biodistribution: CP newborn rabbit model (i.v.) • Increased circulation time comparing to G4 • Brain uptake higher than G4 • Extent of dendrimer uptake correlated with the extent of disease Cellular uptake: BV2 microglial cells • Maximal Dendrimer uptake (resting): 0.038 ± 0.03 pg/cell • 6.25-fold increase in maximal dendrimer uptake by LPS stimulation (0.377 ± 0.01 pg/cell) | [175,176] | |
G3/G4 CCPD (48/96) | -NHEt (+) | in vitro | In vitro • Decreased TNF-α release in LPS-activated BV-2 cells, to the same extent as NAC. • No differences in the anti-inflammatory properties between G3 and G4 • Scavenger capacity of DPPH free radicals • Exhibit reduction capacity of ferric ions. G4 had a stronger reduction capacity than G3 | [24] | |
PEGOL-60 (60) | -OH (0) | in vivo/ in vitro | Biodistribution: CP newborn rabbit model (i.v.) • 10-fold higher brain uptake than age-matched healthy kits • Co-localization with activated microglia within 1h post-administration • No co-localization with activated microglia in healthy controls | In vitro • Co-treatment with LPS led to a significant downregulation in TNF-α, IL-6, IL-10, and iNOS, and upregulation in CD206, Arg1, IL-4 • Significant reduction in excreted TNF-α and NO in LPS-activated BV2 microglial • Pre-treatment resulted in a significant improvement in cellular viability upon a H2O2 challenge in BV2 microglial cells. | [178] |
G0/G1 “Click dendrimers” (3 or 6) | -OH (0) | in vitro | In vitro • Reduction of NO release in LPS-activated N9 microglial cells • Inhibition of PGE2 in LPS-activated N9 microglial cells • Higher anti-inflammatory effect of G1 than G0 | [179] | |
-Acetylene (0) | in vitro | In vitro • Reduction of NO release in LPS-activated N9 microglial cells only at the highest concentration (50 µM) • Inhibition of PGE2 in LPS-activated N9 microglial cells • Lower anti-inflammatory effect of G1 than G0 | [179] | ||
dPG (64) | -OH (0) | in vivo/ in vitro | Cellular uptake • Increased cellular uptake with increased size in Macrophage-differentiated THP-1 cells • Lower particle uptake than negative dPGS for similar sized particles in Macrophage-differentiated THP-1 cells | in vivo TLR2-/GFAP-luciferase transgenic mice—i.n. with LPS • dPG could not suppress the LPS-activated effects on microglia and astrocytes Mouse Organotypic Hippocampal Brain Slices • Did not prevent spine loss caused by an Aβ insult in vitro • Three-hour pre-treatment did not change the mitochondrial activity, NO nor the cytokine release in LPS-activated N9 neonatal murine microglia cells | [131,164,180,181] |
-OSO3− (−) | in vivo/ in vitro | Cellular uptake • Selectively taken up by microglial cells and not astrocytes or neurons in Mouse Organotypic Hippocampal Brain Slices • Higher uptake by microglia than astrocytes in mixed mouse cortical cultures • Higher particle uptake than neutral dPG for similar sized particles in macrophage-differentiated THP-1 cells • Increased cellular uptake with increased size in macrophage-differentiated THP-1 cells | in vivo TLR2-/GFAP-luciferase transgenic mice—i.n. with LPS • Reduction of microglial activation (but not astrocyte activation) in a concentration and time-dependent manner Mouse model of complement activation • Pre-treatment reduced C5a generation in a LPS-stimulated mice Mouse contact dermatitis model • Reduced leukocyte extravasation to inflamed tissue in vitro • Act as a scavenger for IL-6 and LCN2 • Directly bind to L-selectin, P-selectin, complement factor C3 and C5 • Three-hour pre-treatment inhibited the reduction of mitochondrial activity of LPS-activated N9 cells in ~25% • Three-hour pre-treatment decreased the release of NO, TNF-α and IL-6, and reduced the nitrosylated proteins in LPS-activated N9cells • Decreased the amount of Aβ internalized by neuroglia in mixed mouse cortical cultures Mouse Organotypic Hippocampal Brain Slices • Three-hour pre-treatment decreased the release of NO, TNF-α and IL-6 in LPS-activated slices • Three-hour pre-treatment prevented spine loss caused by LPS stimulation. • Avoided the morphological changes on postsynaptic dendritic spines of an Aβ (1-42) insult. • Reduced LCN2 production in Aβ-exposed slice, comparing to Aβ (1-42) incubation alone | [131,163,164,180,181] | |
G1 PPH (10/12) | -N(CH2P(O)(OH)(ONa))2 (ABP) (−) | in vivo/ in vitro | In vivo Mouse arthritis model (IL-1-ra−/−)—i.v. • Completely inhibited inflammation and arthritis at doses of 1 and 10 mg/kg • Decreased serum concentrations of IL-1β, TNF-α, IL-6, and IL-17 and the amount of MMP3 and MMP9 K/BxN serum transfer mouse model—i.v. • Prevented inflammation and arthritis In vitro • Activate human monocytes in an alternative pathway • Human monocytes remained viable longer than control monocytes, underwent phenotypical changes and increased NF-kB. • Skew mice splenocytes towards an anti-inflammatory phenotype, as it increased their production of anti-inflammatory cytokines (IL-4 and IL-10) and reduced the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-17, IL-2, INF-γ) | [165,169,182,183,184] | |
-CH(NHMe)(P(O)(OH)(ONa)) (AMP) (−) | in vivo | In vivo Mouse arthritis model (IL-1-ra−/−)—i.v. • Did not change paw swelling and in arthritis score | [169] | ||
-COONa | in vitro | In vitro • Lower activation of human monocytes than dendrimers ending with phosphonic acid groups | [182] | ||
G1 PPH (2,4,6,8,16) | -N(CH2P(O)(OH)(ONa))2 (ABP) (-) | in vivo/ in vitro | In vivo K/BxN serum transfer mouse model—i.v. • Could not prevent inflammation and arthritis. In vitro • G1 PPH (2,4,6): Lower activity towards human monocytes than ABP-12 • G1 PPH (8): Most bioactive dendrimer to activate human monocytes • G1 PPH (16): Similar activity towards human monocytes to ABP-12 | [183,184] | |
G3/G4 PPH (48/96) | -N(CH2P(O)(OCH3)2)2 (0) | In vivo Mouse air pouch injected with zymosan—i.v. • Reduced the number of migrating cells into the pouch • Decreased NO levels and reduced the iNOS and CD86 expression in infiltrating cells and cells lining the air pouch cavity. CD163 expression was restored in these cells. • Able to modulate M1/M2 ratio in vivo In vitro • Reduced NO, TNF-α and IL-1β release and prevent IL-4 decrease in LPS-activated mouse peritoneal macrophages. G4 > G3. • Reduced iNOS and CD86 expression in LPS-activated mouse peritoneal macrophages G4 > G3 • Prevent macrophages polarization to M1 state and return the M1/M2 balance. • Similar anti-inflammatory properties on monocyte-derived human macrophages | [170] | ||
G1 Carbosilane (8) | -N(CH2P(O)(OH)(ONa))2 (ABP) (−) | in vitro | In vitro • Good activity in alternatively-activation of human monocytes | [185] | |
G2 PPI (8) | -N(CH2P(O)(OH)(ONa))2 (ABP) (−) | in vivo/ in vitro | In vivo Mouse arthritis model (IL-1-ra−/−)—i.v. • Did not change paw swelling and in arthritis score In vitro • Did not activate human monocytes | [169,185] | |
G1/G2 PAMAM (4/8) | -N(CH2P(O)(OH)(ONa))2 (ABP) (−) | in vitro | In vitro • Did not activate human monocytes | [185] | |
G2 PLL (8) | -N(CH2P(O)(OH)(ONa))2 (ABP) (−) | in vitro | In vitro • Did not activate human monocytes | [185] |
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Moreira, D.A.; Santos, S.D.; Leiro, V.; Pêgo, A.P. Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease. Pharmaceutics 2023, 15, 1054. https://doi.org/10.3390/pharmaceutics15041054
Moreira DA, Santos SD, Leiro V, Pêgo AP. Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease. Pharmaceutics. 2023; 15(4):1054. https://doi.org/10.3390/pharmaceutics15041054
Chicago/Turabian StyleMoreira, Débora A., Sofia D. Santos, Victoria Leiro, and Ana P. Pêgo. 2023. "Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease" Pharmaceutics 15, no. 4: 1054. https://doi.org/10.3390/pharmaceutics15041054