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Due to the body's systemic distribution of photothermal agents (PTAs), and to the imprecise exposure of lasers, photothermal therapy (PTT) is challenging to use in treating tumor sites selectively. Striving for PTT with high selectivity and precise treatment is nevertheless important, in order to raise the survival rate of cancer patients and lower the likelihood of adverse effects on other body sections. Here, we studied cold atmospheric plasma (CAP) as a supplementary procedure to enhance selectivity of PTT for cancer, using the classical photothermic agent's gold nanostars (AuNSs). In in vitro experiments, CAP decreases the effective power of PTT: the combination of PTT with CAP at lower power has similar cytotoxicity to that using higher power irradiation alone. In in vivo experiments, combination therapy can achieve rapid tumor suppression in the early stages of treatment and reduce side effects to surrounding normal tissues, compared to applying PTT alone. This research provides a strategy for the use of selective PTT for cancer, and promotes the clinical transformation of CAP.
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Neoplasias , Fotoquimioterapia , Gases em Plasma , Línea Celular Tumoral , Oro/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fototerapia , Terapia Fototérmica , Gases em Plasma/farmacología , Gases em Plasma/uso terapéuticoRESUMEN
Disruption of vulnerable atherosclerotic plaques often leads to myocardial infarction and stroke, the leading causes of morbidity and mortality in the United States. A diagnostic method that detects high-risk atherosclerotic plaques at early stages could prevent these sequelae. The abundance of immune cells in the arterial wall, especially inflammatory Ly-6Chi monocytes and foamy macrophages, is indicative of plaque inflammation, and may be associated with plaque vulnerability. Hence, we sought to develop a new method that specifically targets these immune cells to offer clinically-relevant diagnostic information about cardiovascular disease. We combine ultra-selective nanoparticle targeting of Ly-6Chi monocytes and foamy macrophages with clinically-viable photoacoustic imaging (PAI) in order to precisely and specifically image inflamed plaques ex vivo in a mouse model that mimics human vulnerable plaques histopathologically. Within the plaques, high-dimensional single-cell flow cytometry (13-parameter) showed that our nanoparticles were almost-exclusively taken up by the Ly-6Chi monocytes and foamy macrophages that heavily infiltrate plaques. PAI identified inflamed atherosclerotic plaques that display ~6-fold greater signal compared to controls (P<0.001) six hours after intravenous injection of ultra-selective carbon nanotubes, with in vivo corroboration via optical imaging. Our highly selective strategy may provide a targeted, non-invasive imaging strategy to accurately identify and diagnose inflamed atherosclerotic lesions.
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Herein, we report a ligand-reversible-shielding strategy based on the mutual shielding of dual ligands tethered to the surface of nanoparticles. To exemplify this concept, phenylboronic acid-functionalized poly(ethylene glycol)- b-poly(ε-caprolactone) (PBA-PEG-PCL) and galactose-functionalized diblock polymer (Gal-PEG-PCL) were mixed to form dual-ligand micelles (PBA/Gal). PBA and Gal residues could form a complex at pH 7.4 and mutually shield their targeting function. At pH 6.8, the binding affinity between PBA and Gal weakened, and PBA preferred to bind with the sialic acid residues on the tumor cell surface rather than to Gal on the micellar surface; furthermore, the unbound Gal recovered its targeting ability toward the asialoglycoprotein receptor. When the pH decreased from 7.4 to 6.8, enzyme-linked immunosorbent assays exhibited that the percentage of exposed Gal on the micellar surface increased 1.9-fold, and flow cytometry showed that HepG2 cellular uptake increased 4.3-fold. More importantly, this process was reversible, confirming the reversible shielding and deshielding of dual ligands. With the encapsulation of a photosensitizer, zinc phthalocyanine (ZnPc), the reversible-shielding micelles showed a 48% improvement in the half-life ( t1/2) in blood circulation, a 54% decrease in liver capture, a 40% increase in tumor accumulation, and a 10.3% improvement in the tumor inhibition rate compared to the Gal-coated irreversible micelles. This dual-ligand mutual-shielding strategy provides a new perspective on reversible tumor targeting.
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Portadores de Fármacos/farmacología , Indoles/farmacología , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Ácidos Borónicos/química , Portadores de Fármacos/química , Glicoles de Etileno/química , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Indoles/química , Isoindoles , Lactonas/química , Ligandos , Micelas , Nanopartículas/química , Neoplasias/patología , Compuestos Organometálicos/química , Poliésteres/química , Polietilenglicoles/química , Polímeros/química , Polímeros/farmacología , Compuestos de ZincRESUMEN
The combination therapy of nitric oxide (NO) and anticancer drug was developed for reversing multidrug resistance (MDR). In order to avoid NO release during the blood circulation, and realize pinpointed release in the tumor cells, we designed a tumor-specific NO-release system based on 10-hydroxycamptothecin (HCPT)-loaded charge-reversal chitosan nanoparticles and covalently linked phenylsulfonyl furoxan (glutathione (GSH)-responsive NO donor) on the surface. The results showed that only 6.0% of NO was eventually released under physiology condition (pHâ¯7.4 and 2⯵M GSH) within 8â¯h. In contrast, 93.0% of NO was released within 4â¯h in the presence of 10â¯mM GSH. Western blot result displayed the P-glycoprotein expression was significantly decreased by 50.1%. Hence, this system performed remarkable cytotoxicity in vitro and the highest tumor inhibition rate (79.7%) comparing with free HCPT group (20.7%) in vivo. Such GSH-responsive NO-release system is a promising candidate with prominent therapeutic effect against MDR tumor.
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Quitosano/química , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Glutatión/metabolismo , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Óxido Nítrico/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Muerte Celular , Sinergismo Farmacológico , Endocitosis , Femenino , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
The acidic pH of tumor tissue has been used to trigger drug release from nanoparticles. However, dynamic interactions between tumor pH and vascularity present challenges to optimize therapy to particular microenvironment conditions. Despite recent development of pH-sensitive nanomaterials that can accurately quantify drug release from nanoparticles, tailoring release to maximize tumor response remains elusive. This study hypothesizes that a computational modeling-based platform that simulates the heterogeneously vascularized tumor microenvironment can enable evaluation of the complex intra-tumoral dynamics involving nanoparticle transport and pH-dependent drug release, and predict optimal nanoparticle parameters to maximize the response. To this end, SPNCD nanoparticles comprising superparamagnetic cores of iron oxide (Fe3O4) and a poly(lactide-co-glycolide acid) shell loaded with doxorubicin (DOX) were fabricated. Drug release was measured in vitro as a function of pH. A 2D model of vascularized tumor growth was calibrated to experimental data and used to evaluate SPNCD effect as a function of drug release rate and tissue vascular heterogeneity. Simulations show that pH-dependent drug release from SPNCD delays tumor regrowth more than DOX alone across all levels of vascular heterogeneity, and that SPNCD significantly inhibit tumor radius over time compared to systemic DOX. The minimum tumor radius forecast by the model was comparable to previous in vivo SPNCD inhibition data. Sensitivity analyses of the SPNCD pH-dependent drug release rate indicate that slower rates are more inhibitory than faster rates. We conclude that an integrated computational and experimental approach enables tailoring drug release by pH-responsive nanomaterials to maximize the tumor response.
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Nanopartículas , Neoplasias , Humanos , Doxorrubicina/farmacología , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Concentración de Iones de Hidrógeno , Portadores de Fármacos/farmacología , Liberación de Fármacos , Línea Celular Tumoral , Microambiente TumoralRESUMEN
OBJECTIVES: To characterize the evolution and interspecies transfer of plasmids between Klebsiella pneumoniae and Escherichia coli within a single patient. METHODS: Minimum inhibitory concentrations were measured using broth microdilution assays. Conjugation assays, string tests, and Galleria mellonella infection model experiments were also conducted. Whole-genome sequencing was performed on the Illumina and Nanopore platforms. Antimicrobial resistance determinants, insertion sequences, and virulence factors were identified using ABRicate/ResFinder database, ISFinder, and virulence factor database. Wzi and capsular polysaccharide (KL) were typed using Kleborate and Kaptive. Multi-locus sequence typing (MLST), replicon typing, and single nucleotide polymorphism analyses were conducted using the BacWGSTdb server. RESULTS: The carbapenem-resistant K. pneumoniae 2111KP was characterized as ST11, wzi64, and KL64, with a positive string test result and a relatively high virulence phenotype. Analysis of the 2111KP genome revealed that blaNDM-1 was located in a 268,400-bp IncFIB/IncHI1B/IncX3 conjugative plasmid (p2111KP-1), regulated by IS26, IS5, and ISKox3. p2111KP-1 was also a rmpA2-associated virulence plasmid with an iutA-iucABCD gene cluster and a IS26-mediated multidrug-resistant fusion plasmid, which contained 8-bp (AGCTGCAC or GGCCTTTG) target site duplications. Segments flanked by IS26 of p2111KP-1 were 99.99% identical to a 49,016-bp E. coli plasmid. CONCLUSIONS: This study provided direct evidence of plasmid fusion via IS26 between two different bacterial species within one patient and revealed the process by which genetic elements conferring carbapenem resistance and virulence were simultaneously transferred between these species. It highlights the need for strategic antibiotic use and rigorous monitoring to prevent the plasmid-mediated fusion and transmission of drug-resistance/virulence factors.
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Proteínas de Escherichia coli , Infecciones por Klebsiella , Humanos , Tipificación de Secuencias Multilocus , Klebsiella pneumoniae , Escherichia coli/genética , Infecciones por Klebsiella/microbiología , Plásmidos/genética , Carbapenémicos/farmacología , Factores de Virulencia/genética , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de Escherichia coli/genéticaRESUMEN
Bivalirudin, as a direct thrombin inhibitor, is considered to be safer compared with other anticoagulants, such as heparin; however, relevant data in China are unclear. The present study aimed to compare the safety of bivalirudin and heparin as anticoagulants in Chinese patients who underwent percutaneous coronary intervention (PCI). In the present study, 2,377 patients with ST-segment elevation myocardial infarction (STEMI), unstable angina, non-STEMI or stable coronary artery disease who underwent primary PCI while receiving bivalirudin or heparin (low molecular weight heparin or unfractionated heparin) were reviewed, and then analyzed as the bivalirudin group (n=944) and heparin group (n=1,433). The net adverse clinical events (NACEs) within 30 days were obtained, which were defined as major adverse cardiac and cerebral events (MACCEs) + Bleeding Academic Research Consortium (BARC) grade 2-5 bleeding events. Compared with the heparin group, the incidence of NACEs was reduced in the bivalirudin group (9.3 vs. 13.4%; P=0.003). However, no discrepancy was found in the incidence of MACCEs between the groups (5.9 vs. 7.6%; P=0.116). Moreover, the incidences of BARC 2-5 (4.8 vs. 8.7%; P<0.001) and BARC 3-5 bleeding events (1.9 vs. 4.4%; P=0.001) were decreased in the bivalirudin group compared with the heparin group. Following adjustment using multivariate logistic regression analysis, bivalirudin treatment (vs. heparin treatment) was independently associated with lower risks of NACEs [odds ratio (OR), 0.587; P<0.001], MACCEs (OR, 0.689; P=0.041) and BARC 2-5 (OR, 0.459; P<0.001) and 3-5 bleeding events (OR, 0.386; P=0.002). Overall, the present study demonstrated that bivalirudin decreased the risks of NACEs and bleeding events compared with heparin in Chinese patients who undergo PCI. However, further validation is required.
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Nearly 1.4 billion people worldwide suffer from arterial hypertension, a significant risk factor for cardiovascular disease which is now the leading cause of death. Despite numerous drugs designed to treat hypertension, only ≈14% of hypertensive individuals have their blood pressure under control. A critical factor negatively impacting the efficacy of available treatments is their poor bioavailability. This leads to increased dosing requirements which can result in more side effects, resulting in patient noncompliance. A recent solution to improve dosing and bioavailability issues has been to incorporate drugs into nanoparticle carriers, with over 50 nanodrugs currently on the market across all diseases, and another 51 currently in clinical trials. Given their ability to improve solubility and bioavailability, nanoparticles may offer significant advantages in the formulation of antihypertensives to overcome pharmacokinetic shortcomings. To date, however, no antihypertensive nanoformulations have been clinically approved. This review assesses in vivo study data from preclinical antihypertensive nanoformulation development and testing. Combined, the results of these studies suggest nanoformulation of antihypertensive drugs may be a promising solution to overcome the poor efficacy of currently available antihypertensives, and with further advances has the potential to open paths for new substances that have heretofore been clinically unrealistic due to poor bioavailability.
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Enfermedades Cardiovasculares , Hipertensión , Nanopartículas , Humanos , Antihipertensivos , Presión Sanguínea , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
Integrated preclinical multimodal imaging systems, such as X-ray computed tomography (CT) combined with positron emission tomography (PET) or magnetic resonance imaging (MRI) combined with PET, are widely available and typically provide robustly co-registered volumes. However, separate devices are often needed to combine a standalone MRI with an existing PET-CT or to incorporate additional data from optical tomography or high-resolution X-ray microtomography. This necessitates image co-registration, which involves complex aspects such as multimodal mouse bed design, fiducial marker inclusion, image reconstruction, and software-based image fusion. Fiducial markers often pose problems for in vivo data due to dynamic range issues, limitations on the imaging field of view, difficulties in marker placement, or marker signal loss over time (e.g., from drying or decay). These challenges must be understood and addressed by each research group requiring image co-registration, resulting in repeated efforts, as the relevant details are rarely described in existing publications. This protocol outlines a general workflow that overcomes these issues. Although a differential transformation is initially created using fiducial markers or visual structures, such markers are not required in production scans. The requirements for the volume data and the metadata generated by the reconstruction software are detailed. The discussion covers achieving and verifying requirements separately for each modality. A phantom-based approach is described to generate a differential transformation between the coordinate systems of two imaging modalities. This method showcases how to co-register production scans without fiducial markers. Each step is illustrated using available software, with recommendations for commercially available phantoms. The feasibility of this approach with different combinations of imaging modalities installed at various sites is showcased.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Animales , Ratones , Tomografía Computarizada por Rayos X/métodos , Tomografía de Emisión de Positrones/métodos , Marcadores Fiduciales , Programas Informáticos , Imagen por Resonancia Magnética/métodos , Fantasmas de ImagenRESUMEN
Although bivalirudin has been recently made available for purchase in China, large-scale analyses on the safety profile of bivalirudin among Chinese patients is lacking. Thus, this study aimed to compare the safety profile of bivalirudin and heparin as anticoagulants in Chinese ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). A total of 1063 STEMI patients undergoing PCI and receiving bivalirudin (n=424, bivalirudin group) or heparin (n=639, heparin group) as anticoagulants were retrospectively enrolled. The net adverse clinical events (NACEs) within 30 days after PCI were recorded, including major adverse cardiac and cerebral events (MACCEs) and bleeding events (bleeding academic research consortium (BARC) grades 2-5 (BARC 2-5)). The incidences of NACEs (10.1 vs 15.6%) (P=0.010), BARC 2-5 bleeding events (5.2 vs 10.3%) (P=0.003), and BARC grades 3-5 (BARC 3-5) bleeding events (2.1 vs 5.5%) (P=0.007) were lower in the bivalirudin group compared to the heparin group, whereas general MACCEs incidence (8.9 vs 6.4%) (P=0.131) and each category of MACCEs (all P>0.05) did not differ between two groups. Furthermore, the multivariate logistic analyses showed that bivalirudin (vs heparin) was independently correlated with lower risk of NACEs (OR=0.508, P=0.002), BARC 2-5 bleeding events (OR=0.403, P=0.001), and BARC 3-5 bleeding events (OR=0.452, P=0.042); other independent risk factors for NACEs, MACCEs, or BARC bleeding events included history of diabetes mellitus, emergency operation, multiple lesional vessels, stent length >33.0 mm, and higher CRUSADE score (all P<0.05). Thus, bivalirudin presented a better safety profile than heparin among Chinese STEMI patients undergoing PCI.
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Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Humanos , Heparina/efectos adversos , Estudios Retrospectivos , Antitrombinas/efectos adversos , Infarto del Miocardio con Elevación del ST/cirugía , Intervención Coronaria Percutánea/efectos adversos , Pueblos del Este de Asia , Resultado del Tratamiento , Hirudinas/efectos adversos , Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Fragmentos de Péptidos/efectos adversos , Fibrinolíticos , Proteínas Recombinantes/efectos adversosRESUMEN
Wound infection and excessive exudate can affect the process of wound healing. However, the disadvantage of the anti-microbial wound dressings is that the biological fluids are ineffectively removed. Inspired by making "Chinese Jianbing", a composite wound nano-dressing was developed consisting of a hydrophilic outer layer (chitosan&polyvinyl alcohol: CTS-PVA) and a hydrophobic inner layer (propolis&polycaprolactone: PRO-PCL) by combining casting and electrospinning methods for effective antibacterial and unidirectional removing excess biofluids. In vitro, the composite wound nano-dressing of PRO-PCL and CTS-PVA (PPCP) could strongly inhibit Pseudomonas aeruginosa. Furthermore, PPCP wound dressing had excellent antioxidant properties and blood coagulation index for effective hemostatic. Importantly, it had a preferable water absorption for removing excess biofluid. In vivo, it had anti-inflammatory properties and promoted collagen â preparation, which realized 80% wound healing on day 7. In short, the PPCP wound dressing provides a new direction and option for antibacterial and removes excess biofluid.
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[This corrects the article DOI: 10.3389/fbioe.2022.943695.].
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INTRODUCTION: Hepatocellular carcinoma (HCC) requires complex care coordination. Patient safety may be compromised with untimely follow-up of abnormal liver imaging. This study evaluated whether an electronic case-finding and tracking system improved timeliness of HCC care. METHODS: An electronic medical record-linked abnormal imaging identification and tracking system was implemented at a Veterans Affairs Hospital. This system reviews all liver radiology reports, generates a queue of abnormal cases for review, and maintains a queue of cancer care events with due dates and automated reminders. This is a pre-/post-intervention cohort study to evaluate whether implementation of this tracking system reduced time between HCC diagnosis and treatment and time between first liver image suspicious for HCC, specialty care, diagnosis, and treatment at a Veterans Hospital. Patients diagnosed with HCC in the 37 months before tracking system implementation were compared to patients diagnosed with HCC in the 71 months after its implementation. Linear regression was used to calculate mean change in relevant intervals of care adjusted for age, race, ethnicity, BCLC stage, and indication for first suspicious image. RESULTS: There were 60 patients pre-intervention and 127 post-intervention. In the post-intervention group, adjusted mean time from diagnosis to treatment was 36 days shorter (p = 0.007), time from imaging to diagnosis 51 days shorter (p = 0.21), and time from imaging to treatment 87 days shorter (p = 0.05). Patients whose imaging was performed for HCC screening had the greatest improvement in time from diagnosis to treatment (63 days, p = 0.02) and from first suspicious image to treatment (179 days, p = 0.03). The post-intervention group also had a greater proportion of HCC diagnosed at earlier BCLC stages (p<0.03). CONCLUSIONS: The tracking system improved timeliness of HCC diagnosis and treatment and may be useful for improving HCC care delivery, including in health systems already implementing HCC screening.
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Self-assembled peptides and proteins possess tremendous potential as targeted drug delivery systems and key applications of these well-defined nanostructures reside in anti-cancer therapy. Peptides and proteins can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions such as pH, temperature, ionic strength, as well as host and guest molecular interactions; their countless benefits include good biocompatibility and high loading capacity for hydrophobic and hydrophilic drugs. These self-assembled nanomaterials can be adorned with functional moieties to specifically target tumor cells. Stimuli-responsive features can also be incorporated with respect to the tumor microenvironment. This review sheds light on the growing interest in self-assembled peptides and proteins and their burgeoning applications in cancer treatment and immunotherapy.
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Biopolymers are of prime importance among which gum polysaccharides hold an eminent standing owing to their high availability and non-toxic nature. Gum biopolymers offer a greener alternative to synthetic polymers and toxic chemicals in the synthesis of metal nanostructures. Metal nanostructures accessible via eco-friendly means endow astounding characteristics to gum-based biocomposites in the field of diagnosis and therapy towards cancer diseases. In this review, assorted approaches for the assembly of nanomaterials mediated by gum biopolymers are presented and their utility in cancer diagnosis and therapy, e.g., bioimaging, radiotherapy, and phototherapy, are deliberated to provide a groundwork for future stimulative research.
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Nanoestructuras , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Fototerapia , Polímeros , PolisacáridosRESUMEN
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a complex and unique cancer. At many tertiary care institutions, optimal treatment is planned at a multidisciplinary liver tumor board (MDLTB). This study examined the impact of referral on MDLTB outcomes for patients with HCC. METHODS: Chart review was performed of incident HCC cases presented over 3 years at an American College of Surgeons accredited MDLTB. Internal cases were defined as patients whose care originated within the tertiary care institution of the MDLTB; external cases were defined as patients who received initial care from outside institutions and referred to the tertiary care MDLTB for consultation. Internal and external cases were compared for differences in HCC diagnosis, treatment, and survival. RESULTS: There were 120 internal cases and 163 external cases. Compared with internal cases, external cases took significantly more time to be diagnosed with HCC (4.5 versus 37.5 days, P < .001) and to be discussed at MDLTB (19 versus 53 days, P < .001). Internal cases were more often diagnosed by imaging studies (77.5%), and external cases were more often diagnosed by biopsy (43%) or by consensus of experts at MDLTB (26%). CONCLUSION: Patients with HCC, whose care originated within the tertiary care institution of the MDLTB, were less likely to require biopsy and had shorter time from initial suspicion to diagnosis of HCC. The data suggest that referral of external HCC cases to a tertiary center MDLTB at initial suspicion may limit unnecessary diagnostic procedures, possibly resulting in decreased health care costs and reduced uncertainty for patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Derivación y Consulta , Estudios RetrospectivosAsunto(s)
Glaucoma , Hipertensión Ocular , Humanos , Glaucoma/etiología , Hipertensión Ocular/etiología , Presión IntraocularRESUMEN
Tumor tissue presents much denser and stiffer extracellular matrix (ECM), which can hinder the penetration of most nanoparticles (NPs) and contribute to the tumor cell proliferation. Here, NIR-activated losartan was encapsulated in hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM. The results showed that losartan enhanced the penetration of DOX, 1.47% of the injected dose (ID) of DOX reached the tumor tissues, which was 3.00-fold higher than the control group (0.49%). In addition, as the existence of thermo-sensitive lauric acid, (Losartanâ¯+â¯DOX)@HMPBs could achieve near "zero drug leakage" during blood circulation, so as to reduce the damage of DOX to normal tissues. Furthermore, the animal experiments proved tumor inhibition ability of (Losartanâ¯+â¯DOX)@HMPBs in synergistic of photothermal/chemotherapy, with the tumor growth inhibition rate of 81.3%. Taken together, these findings can be a candidate for developing vectors with enhanced tumor penetration and therapeutic effect in future clinical application. STATEMENT OF SIGNIFICANCE: Due to the existence of denser extracellular matrices (ECM), only 0.7% of the administered nanoparticles dose is delivered to tumor, which will limit the tumors' therapeutic effect. Degradation of ECM can improve the penetration of nanoparticles in tumors. However, no researchers has encapsulated losartan in nanoparticles to degrade ECM. Herein, we developed a NIR induced losartan and DOX co-delivery system based on hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM and improve the penetration of nanoparticles in tumors. The prepared nanoparticles can also acheive near "zero drug leakage" during blood circulation and "fixed-point drug release" in tumor, so as to reduce the damage of DOX to normal tissues. We believe the prepared nanoparticles provide a new platform for cancer treatment.
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Doxorrubicina , Ferrocianuros , Rayos Infrarrojos , Neoplasias Mamarias Experimentales , Nanopartículas , Fototerapia , Animales , Línea Celular Tumoral , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Femenino , Ferrocianuros/química , Ferrocianuros/farmacocinética , Ferrocianuros/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéuticoRESUMEN
Suppressing the angiogenesis in tumors by inhibiting the VEGF/VEGFR2 signaling pathway offers an important approach for cancer therapy. In this work, we developed a heparinoid angiogenesis inhibitor of sulphated chitosan (SCTS), which has a higher inhibitory activity and better safety compared with heparin. It can block the VEGF/VEGFR2 signaling pathway significantly and has a stronger inhibitory effect on the cellular migration and tube formation of HUVECs than heparin in the presence of VEGF in vitro as well. Other than this, SCTS showed an obvious inhibition in tumor size, which was 42.12% higher than the heparin group, and the results of immunohistochemistry showed that the inhibition rate of neovascularization in SCTS was significantly higher than for the heparin control (63.8% vs. 30.7%) at best. In addition, hemorrhage was never observed in the body during the entire process of the experiment, suggesting that it has no obvious anticoagulant activity and possesses good biocompatibility.
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Inhibidores de la Angiogénesis/farmacología , Quitosano/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Quitosano/síntesis química , Quitosano/química , Relación Dosis-Respuesta a Droga , Células Hep G2 , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We previously proved the superiority of the ligand reversible shielding strategy based on the pH-responsive self-assembly/disassembly of gold nanoparticles through computed tomography imaging in vivo. Herein, the practicality of this strategy in tumor therapy was investigated by a ligand reversible shielding system based on a temperature-responsive polymer. The ligand biotin, cisplatin-loaded chain poly(acrylic acid)-Pt, and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm)) were co-modified onto the surface of gold nanostars. In the blood circulation (37⯰C), the ligand was shielded by the extension of P(NIPAAm-co-AAm), whose lower critical solution temperature (LCST) is approximately 39⯰C. After the nanoparticles accumulate at the tumor site by the enhanced permeability and retention (EPR) effect, the heat generated from gold nanostars upon near-infrared light irradiation would trigger the contraction of P(NIPAAm-co-AAm), thus deshielding the ligand for enhanced tumor cellular uptake. Owing to the reversible extension-contraction transformation change of P(NIPAAm-co-AAm), the reversible shielding effect on the ligand could be accomplished even if the nanoparticles return to the blood circulation. The results indicated that the system could extend blood circulation (1.6-fold at 24â¯h), reduce immune system clearance (28% lower), and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. This strategy showed significantly superior tumor inhibition (11% higher) than the irreversible system. All these results make clear that the ligand reversible shielding strategy is effective and offers important references for the design of nanomaterials for improving tumor accumulation. STATEMENT OF SIGNIFICANCE: Herein, the practicality of the ligand reversible shielding strategy in tumor therapy was investigated. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm) which LCST is about 39⯰C) were co-modified onto the surface of gold nanostars. This well-designed NPs could shield target ligand in blood circulation (37⯰C) and deshield it at tumor site (40-41⯰C) reversibly. The results indicated that the system could extend blood circulation (1.6-fold at 24â¯h), reduce immune system clearance (28% lower) and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. Significantly, the strategy showed superior tumor inhibition than the irreversible system (11% higher).