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1.
Nanoscale ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32412575

RESUMO

The bottom-up synthesis of graphene quantum dots (GQDs) using solvothermal methods has attracted considerable attention because of their fewer defects and controllable size/morphology. However, the influence of organic solvents on the preparation of GQDs is still unknown. Herein, a systematic study on the carbonization of organic solvents toward GQDs is reported. The results show that organic solvents with the double bond or benzene ring or double hydrophilic groups could be directly decomposed into GQDs without the addition of catalysts or molecular precursors. The as-synthesized GQDs demonstrate ultra-small size distribution, high stability, tunable excitation wavelength and upconverted fluorescence. Both hematological and histopathological analyses show that the as-synthesized GQDs demonstrate a very good safety profile and excellent biocompatibility. The versatility of this synthesis strategy offers easy control of the surface group, composition, and optical properties of GQDs at the molecular level.

2.
J Control Release ; 323: 253-268, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32333919

RESUMO

Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria both in vitro and in vivo. OMVs are nano-sized spherical vehicles formed by lipid bilayer membranes and contain multiple parent bacteria-derived components. Based on the presence of bacterial antigens, pathogen-associated molecular patterns (PAMPs), adhesins, various proteins and the vesicle structure, OMVs have been developed for biomedical applications as bacterial vaccines, adjuvants, cancer immunotherapy agents, drug delivery vehicles, and anti-bacteria adhesion agents. In this review, we analyze the contributions of the structure and composition of OMVs to their applications, summarize the methods used to isolate and characterize OMVs, and highlight recent progress and future perspectives of OMVs in biomedical applications.

3.
Nat Commun ; 11(1): 1126, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111847

RESUMO

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.

4.
Blood Cancer J ; 10(3): 33, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144237

RESUMO

Bortezomib-based regimens are widely used as induction therapy for multiple myeloma (MM). Unlike lenalidomide, the role of bortezomib in consolidation and maintenance therapy for MM is less clear. We performed a meta-analysis to evaluate the impact of bortezomib-based consolidation and maintenance therapy on survival outcomes and adverse events. PubMed, Web of Science, Embase databases, and major conference proceedings were searched for randomized controlled trials (RCTs) of bortezomib-based regimens as consolidation or maintenance therapy for MM. Ten RCTs enrolling 3147 patients were included in the meta-analysis. Bortezomib-based regimens were compared with regimens without bortezomib or observation. The meta-analysis suggested that bortezomib-based maintenance therapy improved progression-free survival (PFS; hazard ratio [HR] = 0.72, 95% CI 0.55-0.95, P = 0.02) and overall survival (OS; HR = 0.71, 95% CI 0.58-0.87, P = 0.001). Bortezomib-based consolidation therapy improved PFS (HR = 0.77, 95% CI 0.68-0.88, P < 0.001) but not OS (HR = 0.98, 95% CI 0.78-1.24, P = 0.87). Bortezomib-based consolidation/maintenance therapy led to a trend toward increased risk of grade ≥ 3 neurologic symptoms, gastrointestinal symptoms, and fatigue. More research is warranted to further assess the role of bortezomib-based consolidation and maintenance therapy for multiple myeloma.

6.
ACS Nano ; 14(3): 3563-3575, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32053346

RESUMO

Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their in vivo fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface of NPs to understand the in vivo fate of different NPs has been shown to be reliable but complicated and time-consuming. In this work, we establish a simple approach for predicting the in vivo fate of polymeric NPs. We prepared a series of poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) NPs with different protein binding behaviors by adjusting their PEG densities, which were determined by analyzing the serum protein adsorption. We further determined the protein binding affinity, denoted as the equilibrium association constant (KA), to correlate with in vivo fate of NPs. The in vivo fate, including blood clearance and Kupffer cell uptake, was studied, and the maximum concentration (Cmax), the area under the plasma concentration-time curve (AUC), and the mean residence time (MRT) were negatively linearly dependent, while Kupffer cell uptake was positively linearly dependent on KA. Subsequently, we verified the reliability of the approach for in vivo fate prediction using poly(methoxyethyl ethylene phosphate)-block-poly(d,l-lactide) (PEEP-b-PLA) and poly(vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PLA) NPs, and the linear relationship between the KA value and their PK parameters further suggests that the protein binding affinity of polymeric NPs can be a direct indicator of their pharmacokinetics.

8.
Haematologica ; 105(3): 765-773, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31197071

RESUMO

The natural history, prognostication and optimal treatment of Richter transformation developed from chronic lymphocytic leukemia (CLL) are not well defined. We report the clinical characteristics and outcomes of a large series of biopsy-confirmed Richter transformation (diffuse large B-cell lymphoma or high grade B-cell lymphoma, n=204) cases diagnosed from 1993 to 2018. After a median follow up of 67.0 months, the median overall survival (OS) was 12.0 months. Patients who received no prior treatment for CLL had significantly better OS (median 46.3 vs. 7.8 months; P<0.001). Patients with elevated lactate dehydrogenase (median 6.2 vs. 39.9 months; P<0.0001) or TP53 disruption (median 8.3 vs. 12.8 months; P=0.046) had worse OS than those without. Immunoglobulin heavy chain variable region gene mutation, cell of origin, Myc/Bcl-2 double expression and MYC/BCL2/BCL6 double-/triple-hit status were not associated with OS. In multivariable Cox regression, elevated lactate dehydrogenase [Hazard ratio (HR) 2.3, 95% Confidence Interval (CI): 1.3-4.1; P=0.01], prior CLL treatment (HR 2.0, 95%CI: 1.2-3.5; P=0.01), and older age (HR 1.03, 95%CI: 1.01-1.05; P=0.01) were associated with worse OS. Twenty-four (12%) patients underwent stem cell transplant (20 autologous and 4 allogeneic), and had a median post-transplant survival of 55.4 months. In conclusion, the overall outcome of Richter transformation is poor. Richter transformation developed in patients with untreated CLL has significantly better survival. Stem cell transplant may benefit select patients.

10.
Nano Lett ; 20(1): 242-251, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31790598

RESUMO

Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape through multiple mechanisms including suppressing antitumor activities of T lymphocytes. However, therapeutic abrogation of MDSCs often causes severe adverse effects, compensatory recruitment of alternative cell populations, and the multiplicity and complexity of relevant cytokines/receptors. Alternatively, suppressing the expansion and tumor trafficking of MDSCs may be a proficient and safe way for cancer treatment. Here we report that pseudoneutrophil cytokine sponges (pCSs) can disrupt expansion and tumor trafficking of MDSCs and reverse immune tolerance. Coated with plasma membranes of neutrophils phenotypically and morphologically similar to polymorphonuclear MDSCs (PMN-MDSCs), the nanosized pCSs inherited most membrane receptors from the "parental" neutrophils, enabling the neutralization of MDSC-related cytokines. Upon pCSs administration, the expansion of MDSCs and their enrichment in peripheral lymphoid organs and tumors were reduced without the compensatory influx of alternative myeloid subsets. In murine breast cancer and melanoma syngeneic models, pCSs treatment dramatically increased the number of tumor-infiltrating T lymphocytes and restored their antitumor functions. In addition, when pCSs were combined with the programmed cell death protein 1 (PD-1), the immune checkpoint blockade synergistically suppressed tumor progression and prolonged animal survival. Overall, the pseudocell nanoplatform opens up new paths toward effective cancer immunotherapy.

11.
Biomater Sci ; 8(1): 370-378, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31728482

RESUMO

Tumor hypoxia, as a hallmark of most solid tumors, poses a serious impediment to O2-dependent anticancer therapies, such as photodynamic therapy (PDT). Although utilizing nanocarriers to load and transport O2 to tumor tissues has been proved effective, the therapeutic outcomes have been impeded by the low O2 capacity and limited tumor penetration of the nanocarriers. To address these problems, we incorporated perfluorooctyl moieties into nanocarriers to improve the encapsulation of perfluorooctyl bromide via fluorophilic interactions, leading to elevated O2 capacity of the nanocarriers. Meanwhile, to enhance the tumor cell penetrating ability as well as reduce reticuloendothelial system recognition, the nanocarrier was further decorated with a cell-penetrating peptide, which was masked with a protecting group via an acid-labile amide bond for prolonged circulation time and acid-activated cell penetration. The in vitro study demonstrated that, apart from remarkably boosting the photocytoxicity of chlorin 6 (Ce6) at a low dosage, the rationally designed O2@DANPCe6+PFOB could even alleviate the pre-existing tumor hypoxia. After intravenous injection, O2@DANPCe6+PFOB exhibited significant tumor accumulation and retention, and potent tumor growth inhibition compared to traditional PDT. Overall, the O2@DANPCe6+PFOB mediated O2 self-supplemented PDT with tumor acidic microenviornment-activated cell penetration provides a promising strategy in anticancer treatment.

12.
ACS Nano ; 13(10): 11967-11980, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31553168

RESUMO

The deep and inner beds of solid tumors lack lymphocytic infiltration and are subjected to various immune escape mechanisms. Reversing immunosuppression deep within the tumor is vital in clinical cancer therapy, however it remains a huge challenge. In this work, we have demonstrated the use of a second window near-infrared (NIR(II)) photothermal treatment to trigger more homogeneous and deeper immunogenic cancer cell death in solid tumors, thereby eliciting both innate and adaptive immune responses for tumor control and metastasis prevention. Specifically, photothermal transducers with similar components, structures, and photothermal conversion efficiencies, but different absorptions in red light, NIR(I), and NIR(II) biowindows, were constructed by controlling the self-assembly of gold nanoparticles on fluidic liposomes. In vitro, photothermal treatments induced immunogenic cell death (ICD) that were accompanied by the release of damage-associated molecular patterns (DAMPs) regardless of the wavelength of incident lasers. In vivo, NIR(II) light resulted in a more homogeneous release and distribution of DAMPs in the deeper parts of the tumors. With the induction of ICD, NIR(II) photothermal therapy simultaneously triggered both innate and adaptive immune responses and enabled efficient tumor control with 5/8 of the mice remaining tumor-free in the cancer vaccination assay. Additionally, the NIR(II) photothermal treatment in combination with checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Finally, using systemically administered two-dimensional polypyrrole nanosheets as a NIR(II) transducer, we achieved striking therapeutic effects against whole-body tumor metastasis via a synergistic photothermal-immunological response.

13.
Blood Cancer J ; 9(9): 73, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471540

RESUMO

Copy number alterations (CNAs) of 9p24.1 occur frequently in Hodgkin lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), primary central nervous system lymphoma, and primary testicular lymphoma, resulting in overexpression of PD-L1 and sensitivity to PD-1 blockade-based immunotherapy. While 9p24.1 CNA was also reported in diffuse large B-cell lymphoma (DLBCL), little is known about its molecular or clinical significance. In this study, we analyzed the prevalence of 9p24.1 CNA in newly diagnosed DLBCL and examined its association with PD-L1, PD-L2, and JAK2 expression, clinical characteristics, and outcome. We found that 10% of DLBCL cases had CNA of 9p24.1, with 6.5% gains, and 3.5% amplifications. Only the cases with a 9p24.1 amplification had high levels of PD-L1, PD-L2, and JAK2 expression. Gains or amplifications of 9p24.1 were associated with a younger age and the ABC/non-GCB subtype. Compared with DLBCL cases without 9p24.1 CNA, the cases with a 9p24.1 amplification had a trend of better event-free survival. Furthermore, the amplification cases had a gene expression and mutation profile similar to those of PMBCL. Our data suggest that amplification of 9p24.1 identifies a unique subset of DLBCL with clinical and molecular features resembling PMBCL that may be amenable to PD-1 blockade-based immunotherapy.

16.
Biomacromolecules ; 20(8): 3000-3008, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31310511

RESUMO

Protein-polymer conjugation is a clinically validated approach to enhanced pharmacokinetic properties. However, the permanent attachment of polymers often leads to irreversibly reduced protein bioactivity and poor tissue penetration. As such, the use of protein-polymer conjugates for solid tumors remains elusive. Herein, we report a simple strategy using enzyme-activatable and size-shrinkable protein-polypeptide conjugates to overcome this clinical challenge. Briefly, a matrix metalloproteinase (MMP)-responsive peptide sequence is introduced between a therapeutic protein interferon (IFN) and a synthetic polypeptide P(EG3Glu)20. The resulting site-specific MMP-responsive conjugate, denoted as PEP20-M-IFN, can, therefore, release the attached P(EG3Glu)20 to achieve both protein activation and deep penetration into the tumor microenvironment (TME). Compared to a similarly produced nonresponsive analogue conjugate PEP20-IFN, our results find PEP20-M-IFN to show higher bioactivity in vitro, improved tumor retention, and deeper penetration in a MMP2-dependent manner. Moreover, systemic administration of PEP20-M-IFN shows outstanding antitumor efficacy in both OVCAR3 and SKOV3 ovarian tumor models in mice. This work highlights the releasable PEPylation strategy for protein drug potentiation at the TME and opens up new opportunities in clinics for the treatment of malignant solid tumors.

17.
Blood ; 134(16): 1289-1297, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31350266

RESUMO

Some patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell-like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio [HR] = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.


Assuntos
Linfoma Difuso de Grandes Células B/mortalidade , Linfoma/mortalidade , Neoplasias Primárias Múltiplas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Intervalo Livre de Progressão
18.
ACS Nano ; 13(8): 8890-8902, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31291092

RESUMO

Intratumoral glucose depletion-induced cancer starvation represents an important strategy for anticancer therapy, but it is often limited by systemic toxicity, nonspecificity, and adaptive development of parallel energy supplies. Herein, we introduce a concept of cascaded catalytic nanomedicine by combining targeted tumor starvation and deoxygenation-activated chemotherapy for an efficient cancer treatment with reduced systemic toxicity. Briefly, nanoclustered cascaded enzymes were synthesized by covalently cross-linking glucose oxidase (GOx) and catalase (CAT) via a pH-responsive polymer. The release of the enzymes can be first triggered by the mildly acidic tumor microenvironment and then be self-accelerated by the subsequent generation of gluconic acid. Once released, GOx can rapidly deplete glucose and molecular oxygen in tumor cells while the toxic side product, i.e., H2O2, can be readily decomposed by CAT for site-specific and low-toxicity tumor starvation. Furthermore, the enzymatic cascades also created a local hypoxia with the oxygen consumption and reductase-activated prodrugs for an additional chemotherapy. The current report represents a promising combinatorial approach using cascaded catalytic nanomedicine to reach concurrent selectivity and efficiency of cancer therapeutics.

19.
Biomater Sci ; 7(9): 3706-3716, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31187794

RESUMO

Tumor hypoxia, which is indispensable to tumor propagation and therapy resistance, has been one of the most important factors influencing clinical outcomes. To modulate the hypoxia microenvironment, we herein developed reactive oxygen species (ROS)-sensitive arylboronic ester-based biomimetic nanocarriers co-encapsulated with a photosensitizer chlorin e6 (Ce6) and a hypoxia-activated prodrug tirapazamine (TPZp) for tumor-specific release and synergistic photodynamic chemotherapy. In order to bypass macrophage uptake and improve tumor penetration, the nanocarriers were further modified with the red blood cell membrane and iRGD peptide (denoted as NPs@i-RBMCe6+TPZp). After administration, NPs@i-RBMCe6+TPZp exhibited prolonged blood circulation, selective tumor accumulation and excellent penetration into the tumor interior. Upon light irradiation, ROS were generated by Ce6 for photodynamic therapy (PDT), which subsequently caused dissociation of the ROS-responsive nanocarriers. An enhanced therapeutic effect was further achieved through the activation of TPZp in the aggravated local hypoxia microenvironment. The synergistic cancer therapy based on NPs@i-RBMCe6+TPZp significantly suppressed tumor growth with negligible side effects. The biomimetic nanocarriers have great potential to overcome hypoxia-limited PDT, and significantly improve the anticancer efficacy by synergistic tumor-targeted PDT and hypoxia-activated chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/química , Neoplasias da Mama/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Nanopartículas/química , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biomiméticos/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Camundongos , Estrutura Molecular , Nanopartículas/metabolismo , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Tirapazamina/química , Tirapazamina/farmacologia
20.
J Clin Oncol ; 37(21): 1819-1827, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31170029

RESUMO

PURPOSE: In patients with diffuse large B-cell lymphoma (DLBCL), most relapses occur within the first 2 years of diagnosis. We sought to define the rate and outcome of late relapses that occurred after achieving event-free survival at 24 months (EFS24). METHODS: We prospectively followed 1,324 patients with newly diagnosed DLBCL from 2002 to 2015 and treated with immunochemotherapy. Cumulative incidences of late DLBCL and indolent lymphoma relapses were analyzed as competing events. Postrelapse survival was defined as time from first relapse to death from any cause. RESULTS: In 847 patients who achieved EFS24, the cumulative incidence of late relapse was 6.9% at 3 years, 9.3% at 5 years, and 10.3% at 8 years after EFS24. The incidence of DLBCL relapse was similar in patients with DLBCL alone at diagnosis (6.3% at 5 years), compared with patients with concurrent indolent lymphoma at diagnosis (5.2%; P = .46). However, the rate of indolent lymphoma relapse was higher in patients with concurrent indolent lymphoma (7.4% v 2.1% at 5 years; P < .01). In patients with DLBCL alone, the rate of DLBCL relapse was similar in the germinal center B-cell-like (GCB) (4.1% at 5 years) and non-GCB (4.0%; P = .71) subtypes, whereas the rate of indolent lymphoma relapse was higher in patients with the GCB subtype (3.9% v 0.0% at 5 years; P = .02). Postrelapse survival was inferior for patients who relapsed with DLBCL than for those who relapsed with indolent lymphoma (median 29.9 months v unreached; P < .01). CONCLUSION: Patients with DLBCL with a concurrent indolent lymphoma and those with the GCB subtype had a higher rate of late relapse, owing to increased relapses with indolent lymphoma. Patients who relapsed with DLBCL had a worse prognosis than those who relapsed with indolent lymphoma.

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