Use of Polyamidoamine Dendrimers in Brain Diseases
Abstract
:1. Introduction
- Safety of the dendrimer formulation
- Reproducibility in preparing the dendrimer formulation
2. Features of PAMAM Dendrimers Useful for Neuroscience Applications
- High stability
- High water-solubility
- Small size
- Precision
- Presence of cavities
- Surfaces that can be readily modified
3. PAMAM Dendrimers and the Delivery of Small Molecule Drugs and Genes across the Blood Brain Barrier
4. Delivery of Small Molecules
- Carbamazepine (CBZ), an anti-epileptic drug, was shown to enhance autophagy and protect against neurodegeneration in vivo. However, it is poorly soluble in water and shows unpredictable pharmacokinetic profiles. Generation 4.5 carboxyl-terminated dendrimers were loaded with CBZ to yield stable, soluble and safe (as tested on RBCs and zebrafish) formulations for potential applications in the treatment of neurodegenerative diseases associated with toxicity of aggregated proteins such as Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease [30]. No further studies were performed to see if the CBZ-dendrimer formulations were effective for the treatment of these diseases.
- He and co-workers encapsulated doxorubicin into G4 PAMAM dendrimers with surface PEG (PEGylated dendrimers) and the targeting ligands wheat germ agglutinin (WGA) and transferrin (Tf). The BBB-targeting ligands WGA and Tf increased the BBB permeability of the dendrimers. These nanoparticles were < 20 nm in size as measured by electron microscopy and dynamic light scattering. The PAMAM-PEG-WGA-Tf delivered more payload (doxorubicin) at brain tumor sites compared to free drug or dendrimers without Tf and WGA [52].
- Swami and colleagues loaded docetaxel (DTX) into G4 PAMAM dendrimers and covalently attached p-hydroxyl benzoic acid to the surface (pHBA). The pHBA has high affinity to sigma receptors that are predominant in the central nervous system. The G4-pHBA-DTX dendrimers were more effective in killing glioblastoma cells and delivered more DTX to the brain compared to free drug [53].
- Microtubule inhibitors (estramustine and podophyllotoxin), covalently attached to PAMAM dendrimers, were found to be more effective in killing glioma cells compared to free drug [56].
- Teow and colleagues conjugated paclitaxel and lauryl chains on the surface of a G3 PAMAM dendrimer. The conjugates showed increased cytotoxicity and permeability across porcine brain endothelial cells [57].
- Sharma and colleagues found that minocycline, conjugated to G6 hydroxyl-terminated PAMAM dendrimers via amide linkages, reduced neuroinflammation in vivo when compared to free minocycline and did so at lower dosages, thus reducing potential drug toxicity [58].
- Kannan and colleagues conjugated N-acetyl-l-cysteine to a G4 hydroxylated PAMAM dendrimer via disulfide linkages, which could be cleaved by intracellular glutathione (GSH). This formulation was shown to reduce motor dysfunction in rabbit models with cerebral palsy when administered postnatally [59].
- Yang and Lopina showed that attaching venlafaxine, a SNRI antidepressant, to PAMAM dendrimer-PEG hydrogels via ester linkages provided an extended release formulation that may help patients with poor drug compliance [60].
- Gamage and colleagues showed that curcumin was conjugated onto a G3-succinamic acid surface dendrimer via ester bonds. This formulation was administered to rats implanted with human glioma cells. The G3-curcumin showed tumor specific distribution, suggesting a potential use for the treatment of brain cancer [61].
5. Delivery of Genes
- One method of attenuating neurodegenerative disease progression is by slowing down the rate of neuronal death. This can be achieved by providing growth factors to the regions of neuronal degeneration, such as brain-derived neurotrophic factor (BDNF), glial-derived neurotropic factor (GDNF) and nerve growth factor (NGF) which are needed for the survival of particular neurons in the brain [72,73]. In HD, lack of BDNF results in the loss of medium spiny neurons of the striatum, a brain region involved in motor, cognitive, and emotional functions. As a result, HD patients present with deterioration in all three of these domains. Examples of this include chorea (an involuntary dance like movement), learning, and memory impairments as well as psychiatric problems. Since the lack of BDNF in the striatum results in the death of these cells, our laboratory has been involved in developing methods to increase BDNF production in the brains of HD rodent models. We have shown that increasing BDNF in HD mice (such as YAC128 and R6/2 models) resulted in the attenuation of motor and cognitive loss [73,74]. Shakhbazau and colleagues found that PAMAM G4 complexed with a plasmid for BDNF significantly increased the secretion of BDNF protein in human bone marrow mesenchymal stem cells (hMSCs), which can be implanted into diseased brains [75]. Although most researchers use charge ratios greater than one, it is interesting that these authors used a charge ratio of 1:1, giving a dendriplex size of about 150–200 nm.
- Similar complexes, formed between G4 and a plasmid for neurotrophin, were successfully used for transfecting human and rodent stem cells [75].
- Huang and colleagues have shown that transferrin conjugated to PAMAM dendrimer-DNA dendriplexes increases gene expression approximately two-fold in the brain compared to dendriplexes that were not conjugated to transferrin [76].
- Additionally, the same researchers have shown in BALB/c mice that conjugating lactoferrin to PAMAM dendrimers with PEG spacers increased brain uptake of the dendrimer 4.6-fold, compared to non-conjugated PAMAM dendrimers and by a 2.2-fold increase compared to dendrimers conjugated to transferrin [77].
- LRP receptors have also been shown to be abundantly expressed in mammalian neuronal cells [78]. Angiopep has been used to target LRP receptors with some specificity [79]. Researchers have shown that gene expression was significantly increased in the cortex, caudate putamen, hippocampus and substantia nigra of BALB/c mice when Angiopep-PEG-PAMAM loaded with DNA was administered, as compared to unconjugated PAMAM loaded with DNA [80].
- Another receptor found on the BBB, the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGFR2R), binds to M6P and IGFR2 at distinct sites. After the binding of M6P-tagged proteins, as well as IGF-2 on those receptors, the molecules may be internalized and sent to lysosomes for degradation [81]. Urayama and colleagues found that this receptor is highly expressed in neonatal mice compared to adult mice. Their findings showed increased uptake of radiolabeled β-glucuronidase in neonatal mice compared to adults, and that this uptake was inhibited by M6P via competitive inhibition [82]. Potentially, conjugating a dendrimer to one of the ligands of the M6P/IGFR2R could be therapeutic for neonatal diseases of the CNS.
- Another targeting ligand for CNS-enhanced drug delivery is the 29 amino-acid rabies virus glycoprotein (RVG29), which allows viral entry into the CNS by binding to nicotinic acetylcholine receptors on neurons [83]. Liu and colleagues have successfully exploited this interaction when RVG29 was conjugated to a PAMAM dendrimer loaded with DNA. They found that this conjugation crossed the BBB more efficiency in vitro, and had a preferential brain accumulation in vivo [84].
- Serramía and colleagues delivered a small siRNA systemically using carbosilane dendrimers targeting astrocytes in BALB/c mice and detected the presence of the dendrimers and the dendriplexes in the brain one hour and 24 hours following injection [85].
6. Fate of PAMAM Dendrimers in Cells
7. Routes of Dendrimer Administration
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Drug(s) | Loading Method | Application | Results |
---|---|---|---|
Carbamazepine | Encapsulation within a G4.5 carboxyl-terminated dendrimer | Neurodegenerative diseases | Decreased neurodegeneration in vivo, decreased protein aggregation, enhanced autophagy, and increased drug solubility [30] |
Curcumin | Covalent linkage to a G3-succinamic acid surface dendrimer via ester bonds | Glioma | Increased delivery in a tumor-specific distribution [61] |
Docetaxel | Encapsulation within G4 PAMAM dendrimers with covalently attached pHBA | Glioblastoma | Increased glioblastoma-cell death, and increased drug delivery to the brain [53] |
Doxorubicin | Encapsulation within PEGylated G4 PAMAM dendrimers with WGA and Tf targeting ligands | Brain tumors | Increased doxorubicin payload at tumor sites [52] |
Estramustine and podophyllotoxin | Covalent linkage to PAMAM dendrimers | Glioma | More effective killing of glioma cells [56] |
Haloperidol | Encapsulation within a G5 PAMAM dendrimer with 1,4-diaminobutane core | Psychiatric | Increased brain and plasma concentrations of haloperidol compared to control formulation in a rat model [67] |
Minocycline | Covalent linkage to G6 hydroxyl-terminated PAMAM dendrimers via amide linkages | Stroke | Reduced neuroinflammation in vivo at lower doses [58] |
N-acetyl-l-cysteine | Covalent linkage to a G4 hydroxylated PAMAM dendrimer via disulfide linkages | Cerebral palsy | Reduced motor dysfunction in rabbit models [59] |
Paclitaxel | Covalent linkage to G3 PAMAM dendrimers with added lauryl chains | Brain tumors | Increased cytotoxicity and permeability across porcine brain endothelial cells [57] |
Risperidone | Encapsulation within a G4 PAMAM dendrimer | Psychiatric | Increased aqueous solubility of risperidone without significant hemolysis or morphological changes to human red blood cells [68] |
Tamoxifen and doxorubicin | Combination encapsulation (tamoxifen) and covalent linkage (doxorubicin) to G4 PAMAM dendrimers with added PEG and Tf | Glioma | Increased accumulation within glioma cells [62] |
Venlafaxine | Covalent linkage to PAMAM dendrimers-PEG hydrogels via ester linkages | Psychiatric | Extended release [60] |
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Florendo, M.; Figacz, A.; Srinageshwar, B.; Sharma, A.; Swanson, D.; Dunbar, G.L.; Rossignol, J. Use of Polyamidoamine Dendrimers in Brain Diseases. Molecules 2018, 23, 2238. https://doi.org/10.3390/molecules23092238
Florendo M, Figacz A, Srinageshwar B, Sharma A, Swanson D, Dunbar GL, Rossignol J. Use of Polyamidoamine Dendrimers in Brain Diseases. Molecules. 2018; 23(9):2238. https://doi.org/10.3390/molecules23092238
Chicago/Turabian StyleFlorendo, Maria, Alexander Figacz, Bhairavi Srinageshwar, Ajit Sharma, Douglas Swanson, Gary L. Dunbar, and Julien Rossignol. 2018. "Use of Polyamidoamine Dendrimers in Brain Diseases" Molecules 23, no. 9: 2238. https://doi.org/10.3390/molecules23092238