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Opis: Treatment of biologically complex diseases, such as cancer, can significantly benefit from combination therapies. These powerful therapies are able to simultaneously target different biological targets, thereby overcoming or reducing drug resistance, decreasing dose-related toxicity, and potentially exhibiting synergistic effects. Herein, we combine the effects of nitric oxide (NO) gas therapy and an anticancer drug Doxorubicin (Dox) using a porous organic polymer (POP) as a delivery vehicle for both. SH-POP, synthesized by a facile, room-temperature method, is rich in both thiol (-SH) and secondary amine (R-NH-R’) functional groups, which can be post-synthetically nitrosylated in a room-temperature reaction that uses water as a solvent, yielding SNO-POP. Fourier-transform infrared (FT-IR) and Raman spectroscopy confirm that both types of functional groups are nitrosylated. Upon white light irradiation, SNO-POP releases up to ~60 µmol of NO per g, and exhibits reversible switch on – switch off NO release behavior triggered by simple light irradiation for at least 20 cycles. Unlike many conventional systems, where a known small-molecule NO donor is incorporated into the pores, here, the porous polymer itself serves as a NO donor, so the pores remain available for the encapsulation of another therapeutic, i.e. Dox. The release of Dox from the Dox@SNO-POP system is pH-sensitive and occurs preferentially in a slightly acidic environment (pH = 5.4). HeLa cancer cell viability studies confirm an enhancement in toxicity that can be ascribed to the synergistic effects of light-triggered NO release and pH-triggered Dox release. Confocal microscopy imaging reveals the presence of both species inside cells. This study is expected to stimulate the development of porous polymers as potent vehicles for combination therapies in cancer treatment and beyond.
Ključne besede: porous organic polymer, nitric oxide, combination therapy, synergistic therapy, chemotherapy
Objavljeno v RUNG: 05.07.2024; Ogledov: 1265; Prenosov: 3
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Opis: The major causes of Diabetes Mellitus Type 2 (T2DM) are multi-factorial consequences of complex interactions between environmental, social and genetic factors. We investigated the genetic risk factors in Slovene patients with T2DM on a model of microvascular complication – Diabetic Retinopathy (DR). Retrospective case-control study includes a T2DM Slovene population with clinical risk factors for T2DM and DR. Only some of the candidate genes with selected single nucleotid polymorphisms (SNPs) were included: (EDN1 (rs5370, rs3087459, rs1476046), EDNRA (rs5335, rs1801708), EDNRB (rs10507875, rs4885493), NOS3 (rs869109213). By genotyping with either real-time polymerase chain reaction or standard polymerase chain reaction (PCR) we successfully identified the contribution of variable number of tandem repeats rs869109213 in DR progression (Proliferative Diabetic Retinopathy (PDR)) in Slovene patients with T2DM. The joint effect of individual genotypes of rs10507875 in EDNRB and rs869109213 in NOS3 on DR onset (DR) and DR progression (PDR) was demonstrated as well. The joint effect of the two polymorphisms on DR onset (DR) and DR progression (PDR) was greater than the individual effect of each polymorphism separately in the analyzed genetic models. Despite genetic research contributions in DR, linkage studies, and Genome-wide association studies the identification of susceptible loci through candidate gene approaches still remains in its early stages. The frequent approach with an ultimate focus on SNP associations with phenotype is likely to underestimate the roles of genetics in human diseases by disregarding not only the joint effect of multiple loci but the complex interaction network between them. By identifying polymorphisms in genetic disorders in a more systematic way, we will be able to deepen our understanding of the regulatory mechanisms and disease etiology which should lead to a more effective development of mechanism-based therapies as well.
Ključne besede: endothelin 1, EDN1, endothelin receptor A, EDNRA, endothelin receptor B, EDNRB, nitric oxide synthase 3, NOS3, diabetic retinopathy, DR, diabetes mellitus type 2, T2DM, polymorphism, SNP, genetic model
Objavljeno v RUNG: 07.09.2018; Ogledov: 4934; Prenosov: 196
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