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1.
Materials (Basel) ; 17(4)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38399069

RESUMO

Blast furnace dust waste (BFDW) proved efficient as a photocatalyst for the decolorization of methylene blue (MB) dye in water. Structural analysis unequivocally identified α-Fe2O3 as the predominant phase, constituting approximately 92%, with a porous surface showcasing unique 10-30 nm agglomerated nanoparticles. Chemical and thermal analyses indicated surface-bound water and carbonate molecules, with the main phase's thermal stability up to 900 °C. Electrical conductivity analysis revealed charge transfer resistance values of 616.4 Ω and electrode resistance of 47.8 Ω. The Mott-Schottky analysis identified α-Fe2O3 as an n-type semiconductor with a flat band potential of 0.181 V vs. Ag/AgCl and a donor density of 1.45 × 1015 cm-3. The 2.2 eV optical bandgap and luminescence stem from α-Fe2O3 and weak ferromagnetism arises from structural defects and surface effects. With a 74% photocatalytic efficiency, stable through three photodegradation cycles, BFDW outperforms comparable waste materials in MB degradation mediated by visible light. The elemental trapping experiment exposed hydroxyl radicals (OH•) and superoxide anions (O2-•) as the primary species in the photodegradation process. Consequently, iron oxide-based BFDW emerges as an environmentally friendly alternative for wastewater treatment, underscoring the pivotal role of its unique physical properties in the photocatalytic process.

2.
Vaccines (Basel) ; 12(2)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38400181

RESUMO

Mucosal vaccines are highly attractive due to high patient compliance and their suitability for mass immunizations. However, all currently licensed mucosal vaccines are composed of attenuated/inactive whole microbes, which are associated with a variety of safety concerns. In contrast, modern subunit vaccines use minimal pathogenic components (antigens) that are safe but typically poorly immunogenic when delivered via mucosal administration. In this study, we demonstrated the utility of various functional polymer-based nanostructures as vaccine carriers. A Group A Streptococcus (GAS)-derived peptide antigen (PJ8) was selected in light of the recent global spread of invasive GAS infection. The vaccine candidates were prepared by either conjugation or physical mixing of PJ8 with rod-, sphere-, worm-, and tadpole-shaped polymeric nanoparticles. The roles of nanoparticle shape and antigen conjugation in vaccine immunogenicity were demonstrated through the comparison of three distinct immunization pathways (subcutaneous, intranasal, and oral). No additional adjuvant or carrier was required to induce bactericidal immune responses even upon oral vaccine administration.

3.
Biomacromolecules ; 25(3): 2007-2015, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38349647

RESUMO

Chemoselective reactions allow near-precision control over the polymer composition and topology to create sequence-controlled polymers with similar secondary and tertiary structures to those found in proteins. Dendrimers are recognized as well-defined macromolecules with the potential to mimic protein surface functionality due to the large number of functional groups available at its periphery with the internal structure acting as the support scaffold. Transitioning from using small-molecule dendrimers to dendritic macromolecules will not only allow retention of the high peripheral functionality but also provide an internal scaffold with a desired polymer composition within each generational layer. Here, we exemplify a systematic approach to creating a dendritic macromolecule with the placement of different polymer building blocks in precise locations within the internal structure and the placement of three different amino acid moieties clustered at the periphery. The synthesis of this ABC dendritic macromolecule was accomplished through iterative chemoselective reactions.


Assuntos
Dendrímeros , Dendrímeros/química , Aminoácidos/química , Polímeros/química , Proteínas
4.
Molecules ; 28(5)2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36903494

RESUMO

Porcine circovirus 2 (PCV2) infection is one of the most serious threats to the swine industry. While the disease can be prevented, to some extent, by commercial PCV2a vaccines, the evolving nature of PCV2 necessitates the development of a novel vaccine that can compete with the mutations of the virus. Thus, we have developed novel multiepitope vaccines based on the PCV2b variant. Three PCV2b capsid protein epitopes, together with a universal T helper epitope, were synthesized and formulated with five delivery systems/adjuvants: complete Freund's adjuvant, poly(methyl acrylate) (PMA), poly(hydrophobic amino acid), liposomes and rod-shaped polymeric nanoparticles built from polystyrene-poly(N-isopropylacrylamide)-poly(N-dimethylacrylamide). Mice were subcutaneously immunized with the vaccine candidates three times at three-week intervals. All vaccinated mice produced high antibody titters after three immunizations as analyzed by the enzyme-linked immunosorbent assay (ELISA), while mice vaccinated with PMA-adjuvanted vaccine elicited high antibody titers even after a single immunization. Thus, the multiepitope PCV2 vaccine candidates designed and examined here show strong potential for further development.


Assuntos
Circovirus , Doenças dos Suínos , Vacinas Virais , Suínos , Animais , Camundongos , Anticorpos Antivirais , Doenças dos Suínos/prevenção & controle , Peptídeos , Epitopos , Adjuvantes Imunológicos
5.
Pharmaceutics ; 15(2)2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36839923

RESUMO

Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant.

6.
Front Pharmacol ; 13: 996053, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386200

RESUMO

K-Ras is a well-studied oncogene, and its mutation is frequently found in epithelial cancers like pancreas, lung, and colorectal cancers. Cancer cells harboring K-Ras mutations are difficult to treat due to the drug resistance and metastasis properties. Cancer stem cells (CSCs) are believed the major cause of chemotherapeutic resistance and responsible for tumor recurrence and metastasis. But how K-Ras mutation affects CSCs and inflammation is not clear. Here, we compared two colon cancer cell lines, HCT-116 and HT-29, with the former being K-RasG13D mutant and the latter being wildtype. We found that HCT-116 cells treated with a K-Ras mutation inhibitor S7333 formed significantly more tumor spheroids than the untreated control, while the wild type of HT-29 cells remained unchanged. However, the size of tumor spheroids was smaller than the untreated controls, indicating their proliferation was suppressed after S7333 treatment. Consistent with this, the expressions of stem genes Lgr5 and CD133 significantly increased and the expression of self-renewal gene TGF-ß1 also increased. The flow cytometry analysis indicated that the expression of stem surface marker CD133 increased in the treated HCT-116 cells. To understand the pathway through which the G13D mutation induced the effects, we studied both RAS/ERK and PI3K/Akt pathways using specific inhibitors SCH772984 and BEZ235. The results indicated that RAS/ERK rather than PI3K/Akt pathway was involved. As CSCs play the initial role in cancer development and the inflammation is a vital step during tumor initiation, we analyzed the correlation between increased stemness and inflammation. We found a close correlation of increased Lgr5 and CD133 with proinflammatory factors like IL-17, IL-22, and IL-23. Together, our findings suggest that K-RasG13D mutation promotes cancer cell growth but decreases cancer stemness and inflammation thus tumorigenesis and metastasis potential in colon cancer. Inhibition of this mutation reverses the process. Therefore, care needs be taken when employing targeted therapies to K-RasG13D mutations in clinics.

7.
Materials (Basel) ; 15(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36363134

RESUMO

Poly(3-hydroxybutyrate) (PHB)-based films containing Poly(ethylene glycol) (PEG), esterified sodium alginate (ALG-e) and polymeric additives loaded with Ag nanoparticles (AgNPs) were obtained by a conventional casting method. AgNPs were produced in aqueous suspension and added to polymeric gels using a phase exchange technique. Composite formation was confirmed by finding the Ag peak in the XRD pattern of PHB. The morphological analysis showed that the inclusion of PEG polymer caused the occurrence of pores over the film surface, which were overshadowed by the addition of ALG-e polymer. The PHB functional groups were dominating the FTIR spectrum, whose bands associated with the crystalline and amorphous regions increased after the addition of PEG and ALG-e polymers. Thermal analysis of the films revealed a decrease in the degradation temperature of PHB containing PEG/AgNPs and PEG/ALG-e/AgNPs, suggesting a catalytic effect. The PHB/PEG/ALG-e/AgNPs film combined the best properties of water vapor permeability and hydrophilicity of the different polymers used. All samples showed good antimicrobial activity in vitro, with the greater inhibitory halo observed for the PEG/PEG/AgNPs against Gram positive S. aureus microorganisms. Thus, the PHB/PEG/ALG-e/AgNPs composite demonstrated here is a promising candidate for skin wound healing treatment.

8.
Nanomaterials (Basel) ; 12(16)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-36014752

RESUMO

ZnO nanocrystals with three different morphologies have been synthesized via a simple sol-gel-based method using Brosimum parinarioides (bitter Amapá) and Parahancornia amapa (sweet Amapá) latex as chelating agents. X-ray diffraction (XRD) and electron diffraction patterns (SAED) patterns showed the ZnO nanocrystals were a pure hexagonal wurtzite phase of ZnO. XRD-based spherical harmonics predictions and HRTEM images depicted that the nanocrystallites constitute pitanga-like (~15.8 nm), teetotum-like (~16.8 nm), and cambuci-like (~22.2 nm) shapes for the samples synthesized using bitter Amapá, sweet Amapá, and bitter/sweet Amapá chelating agent, respectively. The band gap luminescence was observed at ~2.67-2.79 eV along with several structural defect-related, blue emissions at 468-474 nm (VO, VZn, Zni), green emissions positioned at 513.89-515.89 (h-VO+), and orange emission at 600.78 nm (VO+-VO++). The best MB dye removal efficiency (85%) was mainly ascribed to the unique shape and oxygen vacancy defects found in the teetotum-like ZnO nanocrystals. Thus, the bitter Amapá and sweet Amapá latex are effective chelating agents for synthesizing distinctive-shaped ZnO nanocrystals with highly defective and remarkable photocatalytic activity.

9.
Biomacromolecules ; 23(9): 3960-3967, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-35994316

RESUMO

Continued SARS-CoV-2 transmission among the human population has meant the evolution of the virus to produce variants of increased infectiousness and virulence, coined variants of concern (VOCs). The last wave of pandemic infections was driven predominantly by the delta VOC, but because of continued transmission and adaptive mutations, the more highly transmissible omicron variant emerged and is now dominant. However, due to waning immunity and emergence of new variants, vaccines alone cannot control the pandemic. The application of an antiviral coating to high-touch surfaces and physical barriers such as masks are an effective means to inactivate the virus and their spread. Here, we demonstrate an environmentally friendly water-borne polymer coating that can completely inactivate SARS-CoV-2 independent of the infectious variant. The polymer was designed to target the highly glycosylated spike protein on the virion surface and inactivate the virion by disruption of the viral membrane through a nano-mechanical process. Our findings show that, even with low amounts of coating on the surface (1 g/m2), inactivation of alpha, delta, and omicron VOCs and degradation of their viral genome were complete. Furthermore, our data shows that the polymer induces little to no skin sensitization in mice and is non-toxic upon oral ingestion in rats. We anticipate that our transparent polymer coating can be applied to face masks and many other surfaces to capture and inactivate the virus, aiding in the reduction of SARS-CoV-2 transmission and evolution of new variants of concern.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , COVID-19/prevenção & controle , Humanos , Camundongos , Polímeros , Ratos , SARS-CoV-2/genética , Vírion
10.
Microsc Res Tech ; 85(7): 2526-2536, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35312128

RESUMO

In this study, açaí-loaded kefir microbial films obtained in solutions containing demerara sugar, a low-cost and relatively organic sugar, were prepared. Environmental scanning electron microscopy (ESEM), atomic force microscopy (AFM), stereometric and multifractal analyses were applied to study the influence of the concentration of açaí over the surface morphology as well as its multifractal nature. The ESEM and AFM images showed that low concentrations of acai berry form surface covered by bacteria, while higher concentrations promote yeast growth. The autocorrelation function suggested that the degree of surface anisotropy changes as the concentration of açaí increases, while the Minkowski Functionals confirmed that the sample with the highest content has a different morphology than the samples containing 10-40 ml. The multifractal analysis revealed that the surfaces have a strong multifractal behavior, where the multifractal singularity strength was higher in the sample containing the highest concentration of açaí. The sample with the highest concentration was then mapped to have a greater vertical growth of its spatial patterns. These results prove that image analysis using mathematical tools can be very useful for the characterization of biological-based systems for application in the biomedicine field. We characterized the micromorphology of the 3D surface of the kefir biofilms associated with Acai extract. The 3D surface analysis of the samples was performed using by environmental scanning electron microscope and atomic force microscopy. We determined the multifractal and Minkowski Functionals of the analyzed samples.


Assuntos
Kefir , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Açúcares , Propriedades de Superfície
11.
Angew Chem Int Ed Engl ; 61(11): e202113974, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35043533

RESUMO

Anisotropic Janus ("snowman") nanoparticles with a single protrusion are currently made via the solvent swelling-induced method. Here, we demonstrate without the aid of toxic solvents a generally applicable method for the formation of anisotropic polymer nanoparticles directly in water by controlling polymer mobility through tuning its glass transition temperature (Tg ). Spherical structures, formed immediately after the emulsion polymerization, transformed into uniform tadpoles (with head diameter ≈60 nm and tail length ≈130 nm) through the protrusion of a single cylindrical tail when cooled to a temperature above the Tg of the polymer. Cooling the spheres to below the Tg produced kinetically trapped kettlebell structures that could be freeze-dried and rehydrated without any structural change. These unique kettlebells could transform into uniform tadpoles by heating above the Tg , representing a triggered and on-demand structural reorganization.

12.
Food Chem ; 373(Pt B): 131521, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34775201

RESUMO

A novel electrochemical sensor based on activated biochar (AB4) and reduced graphene oxide (rGO) was developed and tested for detection of paraquat (PQ) in food samples. Precursor biochar was obtained by the pyrolysis of water hyacinth biomass at 400, 500, and 600 °C, followed by a chemical activation step using HNO3 to increase the amount of oxygenated and nitrogenated groups. The modified electrodes (rGO-AB4) were tested in different experimental conditions, and exhibited good response under the optimized conditions, showing linearity from 0.74 to 9.82 µmol L-1 and a limit of detection and limit of quantification of 0.02 µmolL-1 and 0.07 µmol L-1, respectively. Interfering species such as glyphosate caused insignificant changes in the peak current of paraquat, and the selectivity of the method was tested using blank and spiked samples of coconut water, wastewater, honey, lettuce and lemon. Recovery ranged from 87.70±2.07% to 103.80±3.94%.


Assuntos
Grafite , Nanocompostos , Técnicas Eletroquímicas , Eletrodos , Limite de Detecção , Paraquat
13.
Biomacromolecules ; 23(1): 174-181, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-34898168

RESUMO

We rationally designed a monomer that when polymerized formed a well-defined nonionic polymer [poly(2-(methacryloyloxy) ethylureido glycinamide), PMEGA] by reversible addition fragmentation chain transfer with a flat and tunable upper critical solution temperature (UCST) in water. The monomer was made in one pot from commercially available compounds and with ease of purification. Strong hydrogen-bonding side groups on the polymer produced sharp coil-to-globule transitions upon cooling below its UCST. Ideal random copolymers produced with butyl methacrylate also showed flat UCST profiles, in which the UCST increased with a greater butyl methacrylate copolymer composition from 7 to 65 °C. In the presence of NaCl, the UCST decreased linearly with NaCl concentration due to the "salting-in" effect, and it was found that the slopes from the linear decrease of UCST were nearly identical for all copolymer compositions. This new polymer and its copolymers support the hypothesis that strong hydrogen bonding between the side groups allowed the flat UCST to be readily tuned with a high level of predictability. We postulate that this polymer system may provide wide biological applicability similar to that found for the well-used flat lower critical solution temperature (LCST) of poly(N-isopropylacrylamide).


Assuntos
Polímeros , Água , Micelas , Polimerização , Temperatura
14.
Cancers (Basel) ; 15(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36612229

RESUMO

Cancer stem cells (CSCs) are primarily responsible for tumour drug resistance and metastasis; thus, targeting CSCs can be a promising approach to stop cancer recurrence. However, CSCs are small in numbers and readily differentiate into matured cancer cells, making the study of their biological features, including therapeutic targets, difficult. The use of three-dimensional (3D) culture systems to enrich CSCs has some limitations, including low sphere forming efficiency, enzymatic digestion that may damage surface proteins, and more importantly no means to sustain the stem properties. A responsive 3D polymer extracellular matrix (ECM) system coated with RGD was used to enrich CSCs, sustain stemness and avoid enzymatic dissociation. RGD was used as a targeting motif and a ligand to bind integrin receptors. We found that the system was able to increase sphere forming efficiency, promote the growth of spheric cells, and maintain stemness-associated properties compared to the current 3D culture. We showed that continuous culture for three generations of colon tumour spheroid led to the stem marker CD24 gradually increasing. Furthermore, the new system could enhance the cancer cell sphere forming ability for the difficult triple negative breast cancer cells, MBA-MD-231. The key stem gene expression for colon cancer also increased with the new system. Further studies indicated that the concentration of RGD, especially at high doses, could inhibit stemness. Taken together, our data demonstrate that our RGD-based ECM system can facilitate the enrichment of CSCs and now allow for the investigation of new therapeutic approaches for colorectal cancer or other cancers.

15.
ACS Nano ; 15(9): 14915-14927, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34423970

RESUMO

The rise in coronavirus variants has resulted in surges of the disease across the globe. The mutations in the spike protein on the surface of the virion membrane not only allow for greater transmission but also raise concerns about vaccine effectiveness. Preventing the spread of SARS-CoV-2, its variants, and other viruses from person to person via airborne or surface transmission requires effective inactivation of the virus. Here, we report a water-borne spray-on coating for the complete inactivation of viral particles and degradation of their RNA. Our nanoworms efficiently bind and, through subsequent large nanoscale conformational changes, rupture the viral membrane and subsequently bind and degrade its RNA. Our coating completely inactivated SARS-CoV-2 (VIC01) and an evolved SARS-CoV-2 variant of concern (B.1.1.7 (alpha)), influenza A, and a surrogate capsid pseudovirus expressing the influenza A virus attachment glycoprotein, hemagglutinin. The polygalactose functionality on the nanoworms targets the conserved S2 subunit on the SARS-CoV-2 virion surface spike glycoprotein for stronger binding, and the additional attachment of guanidine groups catalyze the degradation of its RNA genome. Coating surgical masks with our nanoworms resulted in complete inactivation of VIC01 and B.1.1.7, providing a powerful control measure for SARS-CoV-2 and its variants. Inactivation was further observed for the influenza A and an AAV-HA capsid pseudovirus, providing broad viral inactivation when using the nanoworm system. The technology described here represents an environmentally friendly coating with a proposed nanomechanical mechanism for inactivation of both enveloped and capsid viruses. The functional nanoworms can be easily modified to target viruses in future pandemics, and is compatible with large scale manufacturing processes.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Pandemias , Água
16.
J Med Chem ; 64(10): 6730-6744, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33955740

RESUMO

Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds 3-6. Compound 5 was further optimized via various structure-activity relationship (SAR) exploration methods to 29, a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound 5 led to the identification of a nonacid inhibitor of HAO1, 31, which has weaker potency and increased permeability.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , DNA/química , Bibliotecas de Moléculas Pequenas/química , Oxirredutases do Álcool/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , DNA/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Hiperoxalúria Primária/metabolismo , Hiperoxalúria Primária/patologia , Indóis/química , Indóis/metabolismo , Masculino , Camundongos , Simulação de Acoplamento Molecular , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo , Transaminases/genética , Transaminases/metabolismo
17.
Clin Exp Pharmacol Physiol ; 48(9): 1185-1202, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34046925

RESUMO

Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non-proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.


Assuntos
Células-Tronco Neoplásicas
18.
J Med Chem ; 64(8): 5049-5066, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33844532

RESUMO

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.


Assuntos
DNA/química , Receptor alfa de Estrogênio/metabolismo , Bibliotecas de Moléculas Pequenas/química , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Click , DNA/metabolismo , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/metabolismo , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Feminino , Meia-Vida , Humanos , Indóis/química , Indóis/metabolismo , Cinética , Camundongos , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
19.
ACS Appl Bio Mater ; 4(3): 2490-2501, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35014367

RESUMO

Bone and bone-related diseases are the major cause of mobility hindrance and mortality in humans and there is no effective and safe treatment for most of them, especially, for bone and bone metastatic cancers. Bisphosphonates (BPs) are a group of small-molecule drugs for treating osteoporosis and bone cancers but have a very short half-life in circulation, requiring high doses and long-term repeat use that can cause severe side effects. Previous attempts of using nanoparticles to deliver BPs have issues of drug loading capacity and endosome escape/drug release. The present study reports the direct synthesis of BP nanoparticles by precipitating bone-favorable calcium ions and a third-generation BP, risedronate (Ca-RISNPs), to achieve high drug loading, endosomal release, and strong bone-targeting properties. The Ca-RISNPs are monodispersed with high stability at physiological pH but readily dissociate at endosomal pH conditions. They demonstrate strong penetration ability and uniform distribution in human bone and cartilage tissues and the superior drug and DNA (plasmid and oligo double strand DNA) delivery capacity in bone cells. These NPs also exhibit high specificity in killing tumor-associated macrophages (TAMs) and inhibit TAM-induced tumor cell migration. Collectively, our data indicate that this BP nanodrug platform has a great potential in managing bone-related diseases and cancers as a prolonged BP nanodrug and simultaneously as the bone-targeted drug delivery system.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Doenças Ósseas/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Animais , Antibióticos Antineoplásicos/química , Doenças Ósseas/patologia , Neoplasias Ósseas/patologia , Cálcio/química , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Difosfonatos/química , Doxorrubicina/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Teste de Materiais , Camundongos , Estrutura Molecular , Nanopartículas/química , Tamanho da Partícula , Células RAW 264.7
20.
Biomacromolecules ; 21(11): 4377-4378, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33161722

RESUMO

This special issue of Biomacromolecules highlights research from The International Polymer Colloid Group (IPCG), which was founded in 1972 as a forum for the exchange of ideas and emerging research activities for scientists and engineers from both academia and industry who study or use polymer colloids. The increasing relevance of polymeric structures with colloidal dimensions to biomacromolecules research provided the impetus for organizing this special issue. The IPCG is composed of over 120 researchers from over 20 countries who are elected to membership. Activities comprise annual symposia including a biennial International Polymer Colloid Group Research Conference and a semiannual newsletter that incorporates a summary of recent (including unpublished) research results from our members.


Assuntos
Coloides , Polímeros
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