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Article: Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.

Gebril, Hoda M / Aryasomayajula, Aravind / de Lima, Mariana Reis Nogueira / Uhrich, Kathryn E / Moghe, Prabhas V

2024 Volume 13, Issue 1, Page(s) 2

Abstract: Background: Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The ... ...

Abstract	Background: Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection. Methods: We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results: AM-NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ. Conclusions: The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.
MeSH term(s)	Humans ; Aged ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Microglia/metabolism ; Neuroinflammatory Diseases ; Neuroblastoma/metabolism
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2653701-1
ISSN	2047-9158
ISSN	2047-9158
DOI	10.1186/s40035-023-00393-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Novel salicylic acid-based chemically crosslinked pH-sensitive hydrogels as potential drug delivery systems.

Demirdirek, Bahar / Uhrich, Kathryn E

International journal of pharmaceutics

2017 Volume 528, Issue 1-2, Page(s) 406–415

Abstract: In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for ... ...

Abstract	In this work, salicylic acid (SA), a non-steroidal anti-inflammatory, was chemically incorporated into hydrogel systems to achieve sustained SA release profiles. With its anti-inflammatory properties, sustained release of SA would be relevant for treating diseases such as diabetes and cancer. In this work, SA was chemically incorporated into hydrogel systems via covalent attachment to an itaconate moiety followed by UV-initiated crosslinking using acrylic acid and poly(ethylene glycol) diacrylate. The chemical composition of the hydrogel system was confirmed using FT-IR spectroscopy. The SA-based hydrogels were designed as pH-responsive hydrogels, collapsing at acidic pH (1.2) values and swelling at higher pH (7.4) values for gastrointestinal-specific delivery. The hydrogel systems exhibited a pH-dependent SA release profile: SA release was much slower at pH 1.2 compared to pH 7.4. Under acidic pH conditions, 30wt% SA was released after 24h, whereas 100wt% SA was released in a sustained manner within 24h in pH 7.4 PBS buffer. The pore structure of the gel networks were studied using SEM and exhibit appropriate pore sizes (15-60μm) for physically encapsulating drugs. In addition, rheological studies of the hydrogels proved that these systems are mechanically strong and robust. Mucoadhesive behaviors were confirmed using a Texture Analyzer, the work of adhesion for the hydrogels was around 290 g·mm and the maximum detachment force was around 135g. The SA-based hydrogels demonstrate great potential for oral delivery of bioactives in combination with SA to treat serious diseases such as cancer and diabetes.
Language	English
Publishing date	2017-08-07
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2017.05.047
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Zs.A 1409: Show issues

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Article ; Online: Sustained Release of Salicylic Acid for Halting Peri-Implantitis Progression in Healthy and Hyperglycemic Systemic Conditions: A Gottingen Minipig Model.

Bergamo, Edmara T P / Witek, Lukasz / Ramalho, Ilana Santos / Lopes, Adolfo Coelho de Oliveira / Nayak, Vasudev Vivekanand / Torroni, Andrea / Slavin, Blaire V / Bonfante, Estevam A / Uhrich, Kathryn E / Graves, Dana T / Coelho, Paulo G

ACS biomaterials science & engineering

2024

Abstract: To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus ( ... ...

Abstract	To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus (T2DM) subjects. Eighteen animals were allocated to three groups: (i) control, (ii) MS (diet for obesity induction), and (iii) T2DM (diet plus streptozotocin for T2DM induction). Maxillary and mandible premolars and first molar were extracted. After 3 months of healing, four implants per side were placed in both jaws of each animal. After 2 months, peri-implantitis was induced by plaque formation using silk ligatures. SAPAE polymer was mixed with mineral oil (3.75 mg/μL) and topically applied biweekly for up to 60 days to halt peri-implantitis progression. Periodontal probing was used to assess pocket depth over time, followed by histomorphologic analysis of harvested samples. The adopted protocol resulted in the onset of peri-implantitis, with healthy minipigs taking twice as long to reach the same level of probing depth relative to MS and T2DM subjects (∼3.0 mm), irrespective of jaw. In a qualitative analysis, SAPAE therapy revealed decreased levels of inflammation in the normoglycemic, MS, and T2DM groups. SAPAE application around implants significantly reduced the progression of peri-implantitis after ∼15 days of therapy, with ∼30% lower probing depth for all systemic conditions and similar rates of probing depth increase per week between the control and SAPAE groups. MS and T2DM conditions presented a faster progression of the peri-implant pocket depth. SAPAE treatment reduced peri-implantitis progression in healthy, MS, and T2DM groups.
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.4c00161
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Article ; Online: Salicylic acid-based pH-sensitive hydrogels as potential oral insulin delivery systems.

Demirdirek, Bahar / Uhrich, Kathryn E

Journal of drug targeting

2015 Volume 23, Issue 7-8, Page(s) 716–724

Abstract: Salicylic acid (SA)-based physically crosslinked pH-sensitive hydrogels were developed for oral insulin delivery using various ratios of salicylate-based poly(anhydride-ester) and poly(acrylic acid) (PAA). Pore size, swelling behavior, insulin loading, ... ...

Abstract	Salicylic acid (SA)-based physically crosslinked pH-sensitive hydrogels were developed for oral insulin delivery using various ratios of salicylate-based poly(anhydride-ester) and poly(acrylic acid) (PAA). Pore size, swelling behavior, insulin loading, insulin and SA release rates of the gels were varied by changing PAA concentration. About 50% of insulin was incorporated within all of the hydrogels, with about 4-8% of insulin released in acidic conditions (pH 1.2) over 2 h. In pH simulating the intestine (pH 6.8), 90% of the insulin and 70% of SA were released within 24 h from the hydrogel system. These results suggest that hydrogels enable pH-dependent protein delivery and can be used for oral insulin and SA delivery to benefit diabetes patients.
MeSH term(s)	Acrylic Resins/chemistry ; Administration, Oral ; Animals ; Cross-Linking Reagents/chemistry ; Diabetes Mellitus/drug therapy ; Drug Carriers/chemistry ; Drug Combinations ; Drug Compounding/methods ; Drug Delivery Systems ; Drug Liberation ; Hydrogels ; Hydrogen-Ion Concentration ; Hypoglycemic Agents/administration & dosage ; Hypoglycemic Agents/therapeutic use ; Insulin/administration & dosage ; Insulin/therapeutic use ; Mice ; NIH 3T3 Cells ; Polyanhydrides/chemistry ; Salicylic Acid/administration & dosage ; Salicylic Acid/therapeutic use
Chemical Substances	Acrylic Resins ; Cross-Linking Reagents ; Drug Carriers ; Drug Combinations ; Hydrogels ; Hypoglycemic Agents ; Insulin ; Polyanhydrides ; carbopol 940 (4Q93RCW27E) ; Salicylic Acid (O414PZ4LPZ)
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article
ZDB-ID	1187110-6
ISSN	1029-2330 ; 1061-186X
ISSN (online)	1029-2330
ISSN	1061-186X
DOI	10.3109/1061186X.2015.1073293
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Zs.A 4481: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Cationic Amphiphiles with Specificity against Gram-Positive and Gram-Negative Bacteria: Chemical Composition and Architecture Combat Bacterial Membranes.

Moretti, Alysha / Weeks, Richard M / Chikindas, Michael / Uhrich, Kathryn E

Langmuir : the ACS journal of surfaces and colloids

2019 Volume 35, Issue 16, Page(s) 5557–5567

Abstract: Small-molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug-resistant bacteria. CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death. Discrete ... ...

Abstract	Small-molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug-resistant bacteria. CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death. Discrete structural features of CAms were varied, and structure-activity relationship studies were performed to guide the rational design of potent antimicrobials with desirable selectivity and cytocompatibility profiles. In particular, the effects of cationic conformational flexibility, hydrophobic domain flexibility, and hydrophobic domain architecture were evaluated. Their influence on antimicrobial efficacy in Gram-positive and Gram-negative bacteria was determined, and their safety profiles were established by assessing their impact on mammalian cells. All CAms have a potent activity against bacteria, and hydrophobic domain rigidity and branched architecture contribute to specificity. The insights gained from this project will aid in the optimization of CAm structures.
MeSH term(s)	Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Cations/chemical synthesis ; Cations/chemistry ; Cations/pharmacology ; Cell Membrane/drug effects ; Cells, Cultured ; Gram-Negative Bacteria/cytology ; Gram-Negative Bacteria/drug effects ; Gram-Positive Bacteria/cytology ; Gram-Positive Bacteria/drug effects ; Humans ; Hydrophobic and Hydrophilic Interactions ; Microbial Sensitivity Tests ; Particle Size ; Surface Properties ; Surface-Active Agents/chemical synthesis ; Surface-Active Agents/chemistry ; Surface-Active Agents/pharmacology
Chemical Substances	Anti-Bacterial Agents ; Cations ; Surface-Active Agents
Language	English
Publishing date	2019-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/acs.langmuir.9b00110
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Article: Synthesis and Characterization of 5-Aminosalicylic Acid Based Poly(anhydride-esters) by Solution Polymerization.

Kim, Youngmi / Uhrich, Kathryn E

Journal of polymer science. Part A, Polymer chemistry

2014 Volume 48, Issue 24, Page(s) 6003–6008

Language	English
Publishing date	2014-01-16
Publishing country	United States
Document type	Journal Article
ISSN	0887-624X
ISSN	0887-624X
DOI	10.1002/pola.24381
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Article ; Online: Cargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation.

Banka, Alison L / Guevara, M Valentina / Brannon, Emma R / Nguyen, Nhien Q / Song, Shuang / Cady, Gillian / Pinsky, David J / Uhrich, Kathryn E / Adili, Reheman / Holinstat, Michael / Eniola-Adefeso, Omolola

Nature communications

2023 Volume 14, Issue 1, Page(s) 2462

Abstract: The combination of inflammation and thrombosis is a hallmark of many cardiovascular diseases. Under such conditions, platelets are recruited to an area of inflammation by forming platelet-leukocyte aggregates via interaction of PSGL-1 on leukocytes and P- ...

Abstract	The combination of inflammation and thrombosis is a hallmark of many cardiovascular diseases. Under such conditions, platelets are recruited to an area of inflammation by forming platelet-leukocyte aggregates via interaction of PSGL-1 on leukocytes and P-selectin on activated platelets, which can bind to the endothelium. While particulate drug carriers have been utilized to passively redirect leukocytes from areas of inflammation, the downstream impact of these carriers on platelet accumulation in thromboinflammatory conditions has yet to be studied. Here, we explore the ability of polymeric particles to divert platelets away from inflamed blood vessels both in vitro and in vivo. We find that untargeted and targeted micron-sized polymeric particles can successfully reduce platelet adhesion to an inflamed endothelial monolayer in vitro in blood flow systems and in vivo in a lipopolysaccharide-induced, systemic inflammation murine model. Our data represent initial work in developing cargo-free, anti-platelet therapeutics specifically for conditions of thromboinflammation.
MeSH term(s)	Humans ; Animals ; Mice ; Neutrophils/metabolism ; Inflammation/metabolism ; Thromboinflammation ; Thrombosis/metabolism ; Blood Platelets/metabolism ; Leukocytes/metabolism ; P-Selectin/metabolism
Chemical Substances	P-Selectin
Language	English
Publishing date	2023-04-28
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37990-z
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Article: Location of the Positive Charges in Cationic Amphiphiles Modulates Their Mechanism of Action against Model Membranes

Almeida, Marcio M / Faig, Allison / Perez, Katia R / Riske, Karin A / Uhrich, Kathryn E

Langmuir. 2019 Oct. 07, v. 35, no. 43

2019

Abstract: Synthetic cationic amphiphiles (CAms) with physicochemical properties similar to antimicrobial peptides are promising molecules in the search for alternative antibiotics to which pathogens cannot easily develop resistance. Here, we investigate two types ... ...

Abstract	Synthetic cationic amphiphiles (CAms) with physicochemical properties similar to antimicrobial peptides are promising molecules in the search for alternative antibiotics to which pathogens cannot easily develop resistance. Here, we investigate two types of CAms based on tartaric acid and containing two hydrophobic chains (of 7 or 11 carbons) and two positive charges, located either at the end of the acyl chains (bola-like, B7 and B11) or at the tartaric acid backbone (gemini-like, G7 and G11). The interaction of the CAms with biomimetic membrane models (anionic and neutral liposomes) was studied with zeta potential and dynamic light scattering measurements, isothermal titration calorimetry, and a fluorescent-based leakage assay. We show that the type of molecule determines the mechanism of action of the CAms. Gemini-like molecules (G7 and G11) interact mainly via electrostatics (exothermic process) and reside in the external vesicle leaflet, altering substantially the vesicle surface potential but not causing significant membrane lysis. On the other hand, the interaction of bola-like CAms (B7 and B11) is endothermic and thus entropy-driven, and these molecules reach both membrane leaflets and cause substantial membrane permeabilization, likely after clustering of anionic lipids. The lytic ability is clearly higher against anionic membranes as compared with neutral membranes. Within each class of molecule, longer alkyl chains (i.e., B11 and G11) exhibit higher affinity and lytic ability. Overall, the molecule B11 exhibits a high potential as antimicrobial agent, since it has a high membrane affinity and causes substantial membrane permeabilization.
Keywords	antibiotics ; antimicrobial peptides ; artificial membranes ; calorimetry ; endothermy ; heat production ; hydrophobicity ; light scattering ; lipids ; mechanism of action ; membrane permeability ; models ; pathogens ; surfactants ; tartaric acid ; titration ; zeta potential
Language	English
Dates of publication	2019-1007
Size	p. 14117-14123.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/acs.langmuir.9b02606
Database	NAL-Catalogue (AGRICOLA)

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Article: Cationic Amphiphiles with Specificity against Gram-Positive and Gram-Negative Bacteria: Chemical Composition and Architecture Combat Bacterial Membranes

Moretti, Alysha / Weeks, Richard M / Chikindas, Michael / Uhrich, Kathryn E

Langmuir. 2019 Mar. 19, v. 35, no. 16

2019

Abstract	Small-molecule cationic amphiphiles (CAms) were designed to combat the rapid rise in drug-resistant bacteria. CAms were designed to target and compromise the structural integrity of bacteria membranes, leading to cell rupture and death. Discrete structural features of CAms were varied, and structure–activity relationship studies were performed to guide the rational design of potent antimicrobials with desirable selectivity and cytocompatibility profiles. In particular, the effects of cationic conformational flexibility, hydrophobic domain flexibility, and hydrophobic domain architecture were evaluated. Their influence on antimicrobial efficacy in Gram-positive and Gram-negative bacteria was determined, and their safety profiles were established by assessing their impact on mammalian cells. All CAms have a potent activity against bacteria, and hydrophobic domain rigidity and branched architecture contribute to specificity. The insights gained from this project will aid in the optimization of CAm structures.
Keywords	Gram-negative bacteria ; anti-infective agents ; antimicrobial properties ; chemical composition ; death ; drug resistance ; hydrophobicity ; mammals ; structure-activity relationships ; surfactants
Language	English
Dates of publication	2019-0319
Size	p. 5557-5567.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2005937-1
ISSN	1520-5827 ; 0743-7463
ISSN (online)	1520-5827
ISSN	0743-7463
DOI	10.1021/acs.langmuir.9b00110
Database	NAL-Catalogue (AGRICOLA)

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Article: Synthesis and Characterization of Salicylic Acid-Based Poly(Anhydride-Ester) Copolymers.

Schmeltzer, Robert C / Uhrich, Kathryn E

Journal of bioactive and compatible polymers

2013 Volume 21, Issue 2, Page(s) 123–133

Abstract: A series of poly(anhydride-esters) based on poly(1,10-bis( ...

Abstract	A series of poly(anhydride-esters) based on poly(1,10-bis(
Language	English
Publishing date	2013-04-03
Publishing country	England
Document type	Journal Article
ZDB-ID	54868-6
ISSN	0883-9115
ISSN	0883-9115
DOI	10.1177/0883911506062976
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Zs.A 2306: Show issues

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