RESUMO
Targeted radionuclide therapy (TRT) provides new and safe opportunities for cancer treatment and management with high precision and efficiency. Here we have designed a novel semiconducting polymer nanoparticle (SPN)-based radiopharmaceutical (211At-MeATE-SPN-GIP) for TRT against glucose-dependent insulinotropic polypeptide receptor (GIPR)-positive cancers to further explore the applications of nanoengineered TRT. 211At-MeATE-SPN-GIP was engineered via nanoprecipitation, followed by its functionalization with a glucose-dependent insulinotropic polypeptide (GIP) to target GIPR and deliver 211At for α therapy. The therapeutic effect and biological safety of 211At-MeATE-SPN-GIP were investigated using GIPR-overexpressing human pancreatic cancer CFPAC-1 cells and CFPAC-1-bearing mice. In this work, 211At-MeATE-SPN-GIP was produced with a radiochemical yield of 43% and radiochemical purity of 98%, which exhibited a specifically high uptake in CFPAC-1 cells, inducing cell cycle arrest at the G2/M phase and extensive DNA damage. In the CFPAC-1-bearing tumor model, 211At-MeATE-SPN-GIP exhibited high therapeutic efficiency, with no obvious side effects. The GIPR-specific binding of 211At-MeATE-SPN-GIP combined with effective inhibition of tumor growth and fewer side effects compared to control suggests that 211At-MeATE-SPN-GIP TRT holds great potential as a novel nanoengineered TRT strategy for patients with GIPR-positive cancer.
Assuntos
Astato/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias Pancreáticas/terapia , Polímeros/química , Receptores dos Hormônios Gastrointestinais/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/metabolismo , Neoplasias Experimentais , Ligação Proteica , Radioisótopos , Receptores dos Hormônios Gastrointestinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Antibacterial coating is rapidly emerging as a pivotal strategy for mitigating spread of bacterial pathogens. However, many challenges still need to be overcome in order to develop a smart coating that can achieve on-demand antibacterial effects. In this study, a Staphylococcus aureus (S. aureus) sensitive peptide sequence is designed, and an antibiotic is then conjugated with this tailor-made peptide. The antibiotic-peptide conjugate is then linked to the surface of a titanium implant, where the peptide can be recognized and cleaved by an enzyme secreted by S. aureus. This allows for the release of antibiotics in the presence of S. aureus, thus achieving delivery of an antibacterial specifically when an infection occurs.
Assuntos
Antibacterianos/química , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Titânio/química , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/patogenicidade , Propriedades de Superfície , Titânio/farmacologiaRESUMO
The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu2+-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu2+ into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing 64Cu2+, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
Assuntos
Cobre/química , Hipertermia Induzida , Neoplasias/terapia , Fósforo/química , Fototerapia , Tomografia por Emissão de Pósitrons , Animais , Morte Celular , Linhagem Celular Tumoral , Terapia Combinada , Cobre/farmacocinética , Humanos , Íons , Camundongos , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Oligopeptídeos/química , Fósforo/farmacocinética , Polietilenoglicóis/química , Espectrofotometria Ultravioleta , Nanomedicina TeranósticaRESUMO
The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C-labeled acetylcholine analogues, N-[(11)C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an (18)F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since (18)F, with a longer half-life, has advantages over (11)C. In a preliminary study, a series of N-[(14)C]ethylpiperidin-3-yl or -4-ylmethanol esters (acetyl and propionyl esters) were newly designed and evaluated in vitro regarding the reactivity with and specificity to AChE using purified human enzymes, leading to a novel (18)F-labeled acetylcholine analogue, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the (18)F-labeled candidate showed desirable properties for PET AChE measurement: high brain uptake of the authentic ester, high AChE specificity, a moderate hydrolysis rate, and low membrane permeability (metabolic trapping) of the metabolite.