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1.
Arthritis Rheumatol ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32602200

RESUMO

OBJECTIVES: Coagulopathy is one of the characteristics of critically ill patients with Coronavirus Disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, but their role in COVID-19 remains unclear. We aimed to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 critically ill and 13 non-critically ill patients with COVID-19 were tested for anti-cardiolipin (aCL) and anti-ß2-glycoprotein 1 (aß2GP1) (IgG, IgM, and IgA) and IgG aß2GP1-D1 by the chemiluminescence assay (CIA) and IgM and IgG anti-phosphatidylserine/prothrombin (aPS/PT) by ELISA. RESULTS: aPLs were detected in 47.0% of critically ill patients (31/66), but not in patients with non-critical conditions. IgA aß2GP1 was the most common aPL, present in 28.8% (19/66) critically ill patients, followed by IgA aCL (25.8%,17/66) and IgG aß2GP1 (18.2%,12/66). For multiple aPLs, IgA aß2GP1+IgA aCL was the most common type (22.7%, 15/66), followed by IgA aß2GP1+IgA aCL+ IgG aß2GP1 (15.2%, 10/66). aPLs emerge around 35-39 days post-disease onset. Dynamic analysis of aPLs revealed 4 patterns based on persistence or transient appearance of the aPLs. Patients with multiple aPLs displayed significantly higher incidence of cerebral infarction (p=0.023). CONCLUSIONS: aPLs were common in critically ill patients. Multiple medium or high levels aPLs may help identify patients at risk of developing cerebral infarction. aPLs may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of "COVID-19-induced-APS-like-syndrome". Long-term follow-up on COVID-19 patients positive for aPLs would be of great importance.

4.
Medicine (Baltimore) ; 99(24): e20613, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541496

RESUMO

BACKGROUND: The 2019 novel coronavirus disease has caused a global pandemic with substantial morbidity and mortality. Chinese medicine has been extensively employed in the coronavirus-related pandemic in China. We aim to assess the efficacy and safety of Chinese medicine in treatment of coronavirus-related pneumonia with the updated results of relevant clinical trials. METHODS: Six electronic databases including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP, and SinoMed will be searched to identify randomized controlled trials up to May 2020. Patients diagnosed with coronavirus-related pneumonia including severe acute respiratory syndrome, Middle East respiratory syndrome, and 2019 novel coronavirus disease and administrated with Chinese medicine will be included. The primary outcome is the all cause mortality at the longest follow up available. The second outcomes include the length of stay in hospital and intensive care units, the duration of mechanical ventilation, and adverse events. The pooled effects will be analyzed and reported as risk ratios for dichotomous data using the Mantel-Haenszel method or mean differences for continuous data using the inverse-variance method. Sensitivity and subgroup analyses will be performed to test the robustness of the results and to explore the potential sources of heterogeneities. The Egger test and/or funnel plots will be used for the examination of publication bias. The grades of recommendation assessment, development, and evaluation methodology will be used to summarize the quality of evidence. The trial sequential analysis will be conducted to test whether the meta-analysis has a sufficient sample size after adjustment of the increased type I and II error risks. RESULTS: The evidence to date of Chinese medicine in treatment of coronavirus-related pneumonia will be systematically reviewed and meta-analyzed. CONCLUSION: The relevant studies will be summarized and further evidence will be provided.PROSPERO registration number: CRD42020178879.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Metanálise como Assunto , Fitoterapia , Pneumonia Viral/tratamento farmacológico , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Humanos , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Int Immunopharmacol ; 86: 106694, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32570034

RESUMO

Lung cancer is leading cause of cancer death in the world. Chemotherapy is currently one of the standard treatments for lung cancer. Gemcitabine is a pyrimidine nucleoside drug which has been approved by FDA to treat lung cancer. However, acquired resistance inevitable develops after Gemcitabine treatment, limiting clinical efficacy. Lewis lung carcinoma (LLC) cells were treated with Gemcitabine and cell apoptosis and programmed cell death-ligand 1 (PD-L1) expression were analyzed by flow cytometry. LLC mouse model was established to analysis the proportion and programmed cell death-1 (PD-1) expression of CD8 + T cells. Anti-tumor effect by treating with Gemcitabine and anti-PD-1 antibody was measured through in vivo LLC mouse model. Gemcitabine treatment induces tumor cell apoptosis and PD-L1 expression. Further study showed that Gemcitabine treatment also increases CD8+ and CD4+ T cells proportion, PD-1 and PD-L1 expression in LLC mouse model. Combination therapy with Gemcitabine and αPD-1 not only has strong anti-tumor effect, but also could inhibit postsurgical recurrence of LLC. Our findings demonstrated that the combination therapy of Gemcitabine and αPD-1 is an effective therapeutic strategy for lung cancer.

6.
Adv Ther ; 37(6): 2829-2840, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378072

RESUMO

INTRODUCTION: Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy. METHODS: This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated. RESULTS: Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment. CONCLUSION: Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT. TRIAL REGISTRATION: Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.

9.
Pharmacol Res ; 158: 104885, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32434051

RESUMO

The antioxidant effect weakens the ability of PDT to resist melanoma, and the hypoxic tumor environment further restricts the application of photosensitizers in tumors. Therefore, to enhance the ability of PDT to resist melanoma, we designed a sequential enhanced PDT theranostic platform (Au@MTM-HA). Firstly, the nanotherapeutic platform uses TiO2 as a photosensitizer, which is doped with MnO2 to form a mesoporous MTM. The MTM can continuously provide oxygen, thereby increasing the level of reactive oxygen species (ROS) and reducing the metastatic effect by alleviating tumor hypoxia. Furthermore, the released Au25Sv9 could inhibit the activity of antioxidant defense enzymes and reduce the scavenging of ROS and further enhance the PDT effect. Simultaneously, surface-modified HA could not only recognize CD44 receptor but also act as a sealing agent for carriers. Result: Au@MTM-HA could explosively produce a 3-fold higher ROS and improve the PDT effect. Therefore, this work may provide strong evidence for Au@MTM-HA as a new and promising PDT candidate for the treatment of metastatic melanoma.

10.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(3): 313-318, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32385995

RESUMO

OBJECTIVE: To investigate the different outcomes of two types of acute kidney injury (AKI) according to standard of Kidney Disease: Improving Global Outcomes-AKI (KDIGO-AKI), and to analyze the risk factors that affect the prognosis of intensive care unit (ICU) patients in China. METHODS: A secondary analysis was performed on the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a multicenter prospective study involving 3 063 patients in 22 tertiary ICUs in 19 provinces and autonomous regions of China. The demographic data, scores reflecting severity of illness, laboratory findings, intervention during ICU stay were extracted. All patients were divided into pure AKI (PAKI) and acute on chronic kidney disease (AoCKD). PAKI was defined as meeting the serum creatinine (SCr) standard of KDIGO-AKI (KDIGO-AKISCr) and the estimated glomerular filtration rate (eGFR) at baseline was ≥ 60 mL×min-1×1.73 m-2, and AoCKD was defined as meeting the KDIGO-AKISCr standard and baseline eGFR was 15-59 mL×min-1×1.73 m-2. All-cause mortality in ICU within 28 days was the primary outcome, while the length of ICU stay and renal replacement therapy (RRT) were the secondary outcome. The differences in baseline data and outcomes between the two groups were compared. The cumulative survival rate of ICU within 28 days was analyzed by Kaplan-Meier survival curve, and the risk factors of ICU death within 28 days were screened by Cox multivariate analysis. RESULTS: Of the 3 063 patients, 1 042 were enrolled, 345 with AKI, 697 without AKI. The AKI incidence was 33.11%, while ICU mortality within 28 days of AKI patients was 13.91% (48/345). Compared with PAKI patients (n = 322), AoCKD patients (n = 23) were older [years old: 74 (59, 77) vs. 58 (41, 72)] and more critical when entering ICU [acute physiology and chronic health evaluation II (APACHE II) score: 23 (19, 27) vs. 15 (11, 22)], had worse basic renal function [eGFR (mL×min-1×1.73 m-2): 49 (38, 54) vs. 115 (94, 136)], more basic complications [Charlson comorbidity index (CCI): 3 (2, 4) vs. 0 (0, 1)] and higher SCr during ICU stay [peak SCr for diagnosis of AKI (µmol/L): 412 (280, 515) vs. 176 (124, 340), all P < 0.01]. The mortality and RRT incidence within 28 days in ICU of AoCKD patients were significantly higher than those of PAKI patients [39.13% (9/23) vs. 12.11% (39/322), 26.09% (6/23) vs. 4.04% (13/322), both P < 0.01], while no significant difference was found in the length of ICU stay. Kaplan-Meier survival curve analysis showed that the 28-day cumulative survival rate in ICU in AoCKD patients was significantly lower than PAKI patients (Log-Rank: χ 2 = 5.939, P = 0.015). Multivariate Cox regression analysis showed that admission to ICU due to respiratory failure [hazard ratio (HR) = 4.458, 95% confidence interval (95%CI) was 1.141-17.413, P = 0.032], vasoactive agents treatment in ICU (HR = 5.181, 95%CI was 2.033-13.199, P = 0.001), and AoCKD (HR = 5.377, 95%CI was 1.303-22.186, P = 0.020) were independent risk factors for ICU death within 28 days. CONCLUSIONS: Further detailed classification (PAKI, AoCKD) based on KDIGO-AKISCr standard combined with eGFR is related to ICU mortality in critical patients within 28 days.

11.
Xenobiotica ; : 1-10, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32400275

RESUMO

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold.Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed.A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

12.
Sci Rep ; 10(1): 8326, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32433497

RESUMO

Zero-tillage is one of conservation tillage techniques. In order to investigate the effects of continuous zero-tillage on yield formation and grain 2-acetyl-1-pyrroline (2-AP, key component of fragrant rice aroma) content of fragrant rice, present study was conducted with a six-season field experiment from 2017 to 2019. The conventional tillage (twice puddling with rotary cultivator before transplanting) was set as control (CK) and zero-tillage was set as treatment (ZT). At the first year after applying zero-tillage, yield loss was observed in the ZT treatment which was attributed to the lower effective panicle number per area and grain number per panicle. However, from late season in 2018 to late season in 2019, significant higher grain yield was recorded in ZT than CK. ZT increased the net photosynthetic rate and chlorophyll content (SPAD value) by 6.81-20.77% and 7.23-23.80% in the last three cropping seasons compared with CK. Higher nitrogen, potassium and phosphorus accumulations in plant tissues were also recorded in ZT than CK from late season in 2018 to late season in 2019. Other hand, higher grain 2-AP content was recorded in ZT than CT in the whole six cropping seasons which might be related to the grain proline content. Furthermore, compared with CK, ZT significantly increased the soil organic matter content and the number of bacteria, fungi and actinomycetes in the last three cropping seasons. In conclusion, continuous zero-tillage could improve soil and increase the photosynthesis and nutrient accumulation and finally achieve the improvement of fragrant rice yield.

13.
Clin Rheumatol ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32372293

RESUMO

OBJECTIVE: The etiologies of acute respiratory failure in patients with systemic rheumatic diseases (SRDs) requiring intensive care remain unknown. This study was undertaken to investigate the etiologies and outcomes. METHODS: A medical records review study was performed of 259 adult SRDs patients with respiratory failure admitted to medical ICU across a 5-year period. The etiologies were classified as infection, SRD exacerbation, and undetermined. The factors associated with ICU mortality were identified with multivariate logistic regression analysis. RESULTS: The etiologies of respiratory failure included infection (n = 209, 80.7%), SRD exacerbation (n = 71, 27.4%), and undetermined (n = 21, 8.1%). The most common pathogen was Pneumocystis jirovecii (39.8%), followed by Aspergillus spp. (33.2%), and cytomegalovirus (23.2%). The ICU mortality rate was 59.8%. A high acute physiology and chronic health evaluation II score (OR 1.118, 95% CI 1.054 to 1.186, p < 0.001), a PaO2/FiO2 ratio < 100 mmHg (OR 3.918, 95% CI 2.199 to 6.892, p < 0.001), and a diagnosis of dermatomyositis/polymyositis (OR 4.898, 95% CI 1.949 to 12.309, p = 0.001), vasculitis (OR 3.007, 95% CI 1.237 to 7.309, p = 0.015), and Pneumocystis pneumonia (OR 2.345, 95% CI 1.168 to 4.705, p = 0.016) were associated with increased mortality. CONCLUSIONS: Opportunistic infections and SRD exacerbation were the most common etiologies of acute respiratory failure in patients with SRDs requiring ICU admission, with high ICU mortality. Development of a standard protocol for differential diagnosis in this population might help initiate definitive therapy and improve clinical outcome.Key Points• Infections, especially with opportunistic infections, were the leading cause of acute respiratory failure in critically ill rheumatology patients, with high mortality.• Severity of illness, certain types of rheumatic diseases, and opportunistic fungal infections were associated with increased mortality.• Using a comprehensive diagnostic workup might help to confirm the infective etiology and improve outcome.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32247185

RESUMO

Antimicrobial activity of cefoperazone, a high protein bound cephalosporin, depends on its unbound concentration. However, the protein binding data of cefoperazone in children is limited, making it challenging to optimize antimicrobial therapy in pediatric clinical practice. Furthermore, a validated method to measure the free part in children is unavailable with the small volume of samples that can be obtained. Therefore, in the present study, we developed and validated an LC-MS/MS method for the determination of free cefoperazone in children. In this study, 70 µL of plasma was used to prepare the ultrafiltrate (only containing the free drug). Chromatographic separation of the analyte was achieved on a C18 column using gradient elution with a mobile phase of acetonitrile and water (0.1% formic acid). Negative electrospray ionisation in the multiple reaction monitoring mode was applied for the detection of cefoperazone and ceftiofur (internal standard). The calibration curve was prepared in the range of 5-5000 ng/mL with excellent linearity. For each level of quality control samples, the intra- and inter-day precision (CV) was below 9.0%, and the accuracy ranged from 91.5% to 105.0%. The matrix effect was less than 11.7%, and the recovery was between 92.9% and 95.9% of cefoperazone. The validated method has been successfully applied to the determination of free plasma concentration of cefoperazone in pediatric patients. The results of the unbound fraction showed considerable individual variability (range: 8.1-48.0%). The correlation analysis showed that age and albumin had significant effects on the protein binding of cefoperazone.

17.
Lancet Respir Med ; 8(5): 506-517, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32272080

RESUMO

As coronavirus disease 2019 (COVID-19) spreads across the world, the intensive care unit (ICU) community must prepare for the challenges associated with this pandemic. Streamlining of workflows for rapid diagnosis and isolation, clinical management, and infection prevention will matter not only to patients with COVID-19, but also to health-care workers and other patients who are at risk from nosocomial transmission. Management of acute respiratory failure and haemodynamics is key. ICU practitioners, hospital administrators, governments, and policy makers must prepare for a substantial increase in critical care bed capacity, with a focus not just on infrastructure and supplies, but also on staff management. Critical care triage to allow the rationing of scarce ICU resources might be needed. Researchers must address unanswered questions, including the role of repurposed and experimental therapies. Collaboration at the local, regional, national, and international level offers the best chance of survival for the critically ill.


Assuntos
Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Cuidados Críticos/métodos , Humanos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
J Environ Manage ; 265: 110542, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275249

RESUMO

The system performance, sludge property and microbial community shift were evaluated in a nitrifying sludge (NS) bioreactor for simultaneous treating p-Nitrophenol (PNP) and high ammonia wastewater. After long-term acclimation for 80 days, the removal efficiencies of PNP and NH4+-N reached to 99.9% and 99.5%, respectively. Meanwhile, the effluent PNP gradually decreased from 7.9 to 0.1 mg/L by acclimation of sludge. The particle size of NS increased from 115.2 µm to 226.3 µm accompanied by the decreased zeta potential as a self-protection strategy. The presence of PNP exposure altered the effluent soluble microbial products (SMP) fluorescent components and molecular composition. The increase in the relative abundance of Thauera, Nitrospiraceae and Nitrosomonas indicated the nitrification and denitrification capacities of NS increased, which maybe the PNP cometabolic biodegradation effect. Moreover, Ignavibacteria and Aeromonas were responsible as the dominant bacteria for degrading PNP in the nitrifying system.


Assuntos
Microbiota , Esgotos , Reatores Biológicos , Nitrificação , Nitrogênio , Nitrofenóis
19.
Crit Care Med ; 48(6): e440-e469, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32224769

RESUMO

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.


Assuntos
Infecções por Coronavirus/terapia , Unidades de Terapia Intensiva/organização & administração , Pneumonia Viral/terapia , Guias de Prática Clínica como Assunto/normas , Betacoronavirus , Estado Terminal , Técnicas e Procedimentos Diagnósticos/normas , Humanos , Controle de Infecções/métodos , Controle de Infecções/normas , Unidades de Terapia Intensiva/normas , Pandemias , Respiração Artificial/métodos , Respiração Artificial/normas , Choque/terapia
20.
ACS Appl Mater Interfaces ; 12(18): 20214-20227, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32248684

RESUMO

Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a "nanoenzyme capsule" was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.

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