Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

Síntese e caracterização de nanopartículas de ouro conjugadas com curcumina e seus efeitos na osteoartrite experimental induzida / Synthesis and characterization of gold nanoparticles combined with curcumin and its effects on experimentally induced osteoarthritis

RESUMO: A Osteoartrite (OA) é uma denominação clínica para uma combinação de condições patológicas que envolvem a degeneração progressiva da cartilagem articular e remodelação de osso subcondral. A curcumina, um potente agente anti-inflamatório, têm sido extensivamente estudada, no entanto não oferece boa biodisponibilidade sistêmica. Nanopartículas de ouro (AuNPs) apresentam aplicações potenciais na administração de substâncias terapêuticas aumentando a eficiência do transporte de fármacos. O objetivo deste estudo foi realizar a síntese e caracterização de um sistema conjugando as AuNPs à curcumina e avaliar seu potencial terapêutico em um modelo experimental de OA em camundongos por desestabilização do menisco medial (DMM). As AuNPs foram conjugadas com curcumina e os sistemas foram caracterizados por espectroscopia no UV-VIS, espalhamento de luz dinâmico (DLS) e determinação do potencial zeta. Formou-se 4 grupos de oito animais cada, denominados A, B, C, D que receberam injeção intra-articular de AuNPs, curcumina, AuNP-curcumina e solução fisiológica, respectivamente. Após 7 semanas, a cartilagem da articulação-femoro- tibio-patelar (AFTP) foi avaliada em uma variação de escore de 0 a 24. A conjugação de AuNP-curcumina mostrou boa estabilidade e aplicação terapêutica, mas não diferiu significativamente (P>0,05) dos grupos A e B, no entanto, mostrou menor valor de escore e significância (P<0,001) em relação ao grupo controle. Os resultados deste trabalho mostram a importância do desenvolvimento de novos nanofármacos. Neste caso a conjugação de AuNPs com a curcumina permitiu a obtenção de um nanofármaco com sugestivo potencial para aplicação no tratamento da OA.

ABSTRACT: Osteoarthritis (OA) is the clinical term for a combination of pathological conditions that involve the progressive degeneration of articular cartilage and subchondral bone remodelling. Curcumin, a potent anti-inflammatory agent, has been extensively studied; however, it does not provide good systemic bioavailability. Gold nanoparticles (AuNPs) have potential applications in the administration of therapeutic substances in order to increase the transport efficiency of drugs. The objectives of this study were to explore the synthesis and characterization of a system combining AuNPs with curcumin and evaluate its therapeutic potential in an experimental model of OA in mice by the destabilization of the medial meniscus (DMM). The AuNPs were conjugated with curcumin and the systems were characterized by UV-VIS spectroscopy, dynamic light scattering (DLS), and zeta potential. Four groups of eight animals each were formed and labelled A, B, C, and D, which received intra-articular injections of AuNPs, curcumin, AuNP-curcumin, and physiologic solution, respectively. After seven weeks, the cartilage of the stifle joint (SJ) was rated on a scale ranging from 0 to 24. Combination of AuNP-curcumin demonstrated good stability and therapeutic applications, but it did not differ significantly (P>0.05) from groups A and B. However, the control group had a significantly lower score (P<0.001). Results of this study demonstrated the importance of developing new nanodrugs. In this case, the combination of AuNPs and curcumin yielded the nanodrug effects suggestive of a potential for application in the treatment of OA.