RESUMO
P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR) in cancers severely limit chemotherapeutic efficacy. We recently reported that phosphatidylinositol-3-kinase (PI3K) 110α and 110ß subunits can be novel targets for reversal of P-gp mediated MDR in cancers, and BAY-1082439 as an inhibitor specific for PI3K 110α and 110ß subunits could reverse P-gp-mediated MDR by downregulating P-gp expression in cancer cells. However, BAY-1082439 has very low solubility, short half-life and high in-vivo clearance rate. Till now, nano-system with the functions to target PI3K P110α and P110ß and reverse P-gp mediated MDR in cancers has not been reported. In our study, a tumor targeting drug delivery nano-system PBDF was established, which comprised doxorubicin (DOX) and BAY-1082439 respectively encapsulated by biodegradable PLGA-SH nanoparticles (NPs) that were grafted to gold nanorods (Au NRs) modified with FA-PEG-SH, to enhance the efficacy to reverse P-gp mediated MDR and to target tumor cells, further, to enhance the efficiency to inhibit MDR tumors overexpressing P-gp. In-vitro experiments indicated that PBDF NPs greatly enhanced uptake of DOX, improved the activity to reverse MDR, inhibited the cell proliferation, and induced S-phase arrest and apoptosis in KB-C2 cells, as compared with free DOX combining free BAY-1082439. In-vivo experiments further demonstrated that PBDF NPs improved the anti-tumor ability of DOX and inhibited development of KB-C2 tumors. Notably, the metastasis of KB-C2 cells in livers and lungs of nude mice were inhibited by treatment with PBDF NPs, which showed no obvious in-vitro or in-vivo toxicity.
Assuntos
Antineoplásicos , Neoplasias , Animais , Camundongos , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Camundongos Nus , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , HumanosRESUMO
Photodynamic therapy (PDT) with aggregation-induced emission photosensitizers (AIE-PSs) has attracted increasing attention for their enhanced fluorescence and reactive oxygen species (ROS) generation abilities upon aggregation. However, it is difficult for AIE-PSs to simultaneously achieve long-wavelength excitation (>600 nm) and high singlet oxygen quantum yield, which restricts their application in deep-tissue PDT. In this study, four novel AIE-PSs were developed by appropriate molecular engineering, and their absorption peaks shifted from 478 to 540 nm with a tail extending to 700 nm. Meanwhile, their emission peaks were also moved from 697 nm to 779 nm with a tail extending over 950 nm. Importantly, their singlet oxygen quantum yields successfully increased from 0.61 to 0.89. Moreover, TBQ, the best photosensitizer developed by us, has been successfully applied to image-guided PDT in BALB/C mice bearing 4T1 breast cancer under red light (605 ± 5 nm) irradiation, with IC50 less than 2.5 µM at a low light dose (10.8 J cm-2). The success of this molecular engineering indicates that increasing the number of acceptors is more effective at red-shifting the absorption band of AIE-PSs than increasing the number of donors, and extending the π-conjugation of acceptors will red-shift the absorption-emission band, increase the maximum molar extinction coefficient, and improve the ROS generation ability of AIE-PSs, thus providing a new strategy for the design of advanced AIE-PSs for deep-tissue PDT.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio , Oxigênio Singlete , Camundongos Endogâmicos BALB CRESUMO
Cancer therapeutics are varied and target diverse processes in cancer progression. Photodynamic therapy (PDT), photothermal therapy (PTT), and the inhibition of pro-cancer proteases are non-invasive anticancer therapeutics that attract increasing attentions for their enhanced specificities and milder systemic toxicities compared to traditional therapeutics. These modalities offer advantages to compensate for the shortcomings of their counterparts. For instance, PDT or PTT efficiently eliminates locally confined tumor cells while exhibiting no effect on metastatic tumor cells. In contrast, the inhibition of pro-cancer proteases systemically suppresses the proliferation and metastasis of cancer cells but does not eradicate existing cancer cells. To synergize these therapeutics, we hereby report a versatile nanoparticle that integrates the effects of PDT, PTT, and enzyme-inhibition. This nanoparticle (CIKP-NP) was synthesized by covalently or non-covalently modifying a photothermal nanoparticle with a photosensitizer, a pro-cancer protease inhibitor, and an albumin-binding molecule. After confirming the PDT, PTT, albumin-binding, and enzyme-inhibition properties at the molecular level, we demonstrated that CIKP-NP killed tumor cells through PDT or PTT and suppressed tumor cell invasion through enzyme-inhibition. In addition, through a breast cancer xenograft mouse model, we demonstrated that CIKP-NP suppressed tumor growth by PDT or PTT effect. Notably, the synergism of PDT and PTT significantly enhanced its anticancer efficiency. Furthermore, CIKP-NP significantly suppressed cancer metastasis in a lung metastatic mouse model. Last, biodistribution and the in vivo retention of CIKP-NP confirmed the tumor-targeting property. Beyond demonstrating the anti-tumor and anti-metastatic efficacy of CIKP-NP, our study also suggests a new strategy to synergize multiple anticancer therapeutics.
Assuntos
Neoplasias , Fotoquimioterapia , Animais , Proliferação de Células , Ouro , Camundongos , Camundongos Endogâmicos BALB C , Nanomedicina , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Terapia Fototérmica , Distribuição TecidualRESUMO
Extensively drug-resistant Acinetobacter baumannii (XDR-AB) has raised considerable concerns due to its mortal damage to humans and its high transmission rate of infections in hospitals. However, current antibiotics not only show poor anti-infection effects in vivo but also frequently cause high nephrotoxicity and neurotoxicity. Herein, we report a near-infrared (NIR) light-initiated antimicrobial photodynamic therapy (aPDT) to effectively treat in vivo XDR-AB infections based on photosensitizer (PS) loaded upconversion nanoparticles (UCNPs, LiYF4:Yb/Er). Such nanoagents feature robust NIR triggered UC luminescence and high-efficiency energy transfer from UCNPs to the loaded PS, thereby allowing NIR-triggered generation of reactive oxygen species (ROS) for destroying the bacterial cell membrane. This strategy permits a high antibacterial activity against XDR-AB, resulting in a decline of 4.72 log10 in viability at a dose of 50 µg mL-1 UCNPs-PVP-RB with 980 nm laser irradiation (1 W cm-2). More significantly, we can achieve excellent therapeutic efficacy against deep-tissue (about 5 mm) XDR-AB infections without causing any side effects in the murine model. In brief, such NIR-activated aPDT may open up new avenues for treating various deep-tissue intractable infections.
Assuntos
Acinetobacter baumannii , Elementos da Série dos Lantanídeos , Nanopartículas Metálicas , Nanopartículas , Preparações Farmacêuticas , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
AIMS: The study aims to investigate the effect of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of fibrinolytic process, on blood glucose in type 2 diabetes mellitus (T2DM) and its mechanism. MATERIALS AND METHODS: We developed a highly potent and highly specific PAI-1 inhibitor, named PAItrap3, based on the inactivated urokinase. Meanwhile, a single point mutation of PAItrap3 (i.e., PAItrapNC) was parallelly prepared as negative control. PAItrap3 was intravenously injected into type 2 diabetic (T2D) mice and its effect on metabolic system was evaluated by measuring the levels of blood glucose, PAI-1, and tumor necrosis factor alpha (TNF-α) in T2D mice. KEY FINDINGS: PAItrap3 significantly reduced the high blood glucose level and PAI-1 level in streptozotocin-induced T2D mice. PAItrapNC did not have any hypoglycemic effect at all on T2D mice. Mechanistically, both PAI-1 and TNF-α levels were attenuated by the administration of PAItrap3. In addition, we observed that PAItrap3 reduced the amount of fat droplets in adipocytes. SIGNIFICANCE: These findings provide clear evidence for PAI-1 to participate in inflammation and obesity mediated hyperglycemia, and open up a new prospect for the treatment of T2DM by PAI-1 inhibition.
Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Adipócitos/efeitos dos fármacos , Animais , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangueRESUMO
An alarming worldwide increase in microbial resistance to traditional drugs and classical pharmacophores has spurred the search for new antimicrobial compounds. Antimicrobial photodynamic therapy (aPDT) has recently emerged as an effective modality for the selective destruction of bacteria and other pathogenic microorganisms. However, some of the factors, including the aggregation of the hydrophobic photosensitizer (PS) in aqueous media and the inefficient biodistribution of PS limit its expansion to clinical conditions. In addition, the photoactivation under visible-light irradiation limits the therapeutic effect of aPDT for deep-tissue infection. To overcome these limitations, a PS (ß-carboxyphthalocyanine zinc, CPZ) delivery system with lanthanide-doped upconversion nanoparticles (UCNPs, LiYF4:Yb/Er) and polyvinylpyrrolidone (PVP) was prepared and its antimicrobial (antibacterial and antifungal) activities were investigated. Such a near-infrared (NIR) triggered UCNPs-CPZ-PVP system significantly reduced the aggregation of CPZ and presented a high anti-infectious activity against multi-drug resistant (MDR) bacteria (methicillin-resistant Staphylococcus aureus by 4.7 log10 and MDR Escherichia coli by 2.1 log10) post aPDT (at 50 µg mL-1 UCNPs-CPZ-PVP with 0.5 W cm-2 980 nm light). In particular, UCNPs-CPZ-PVP showed high antifungal efficacy against Candida albicans. In vivo aPDT experiments were further carried out using an MDR bacterial infection murine model in the presence of 5 mm thick tissue specimens, demonstrating the great potential of UCNPs-CPZ-PVP against infections in deep tissue. Altogether, we reveal an efficient NIR-triggered nano-photosensitizer with promising antifungal and antibacterial efficacy for clinical antimicrobial therapy.