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1.
Medicine (Baltimore) ; 100(40): e27359, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622835

RESUMO

ABSTRACT: Uterine diffuse large B-cell lymphoma (DLBCL) is a rare clinical condition. Most studies for uterine DLBCL are derived from case reports and series. Our main objective was to present a new case while also investigating the demographic, clinical characteristics, and survival of women with primary uterine DLBCL as compared to non-uterine DLBCL using the Surveillance, Epidemiology, and End Results incidence database. We queried the Surveillance, Epidemiology, and End Results database for women aged 18 years or older with a diagnosis of primary DLBCL from 1975 to 2017. The most common site of primary uterine DLBCL is the cervix uteri not otherwise specified, followed by endometrium, uterus not otherwise specified, corpus uteri, myometrium and isthmus uteri. Non-uterine DLBCL cases tend to be older than uterine DLBCL cases. Uterine DLBCL is most common among women aged 40 to 64 years. Patients with uterine DLBCL showed greater survival than non-uterine DLBCL patients, and patients treated in the rituximab era also exhibited a survival benefit. Both the elderly and African American cohorts experienced worse overall survival.


Assuntos
Linfoma Difuso de Grandes Células B/mortalidade , Neoplasias Uterinas/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Programa de SEER , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/tratamento farmacológico , Vincristina/uso terapêutico
2.
Anticancer Res ; 41(10): 4715-4718, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593419

RESUMO

BACKGROUND/AIM: Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. MATERIALS AND METHODS: The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. RESULTS: Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. CONCLUSION: CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Phys Chem Chem Phys ; 23(34): 19011-19021, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612439

RESUMO

The design of mixed polymeric micelles by a combination of two or more dissimilar polymers is a potential strategy to achieve multiple stimuli-response for anti-cancer drug delivery. However, their drug loading co-micellization behavior and multiple stimuli-responsive drug release mechanism have been poorly understood at the mesoscopic level, especially in the system that involves reduction-response due to the difficulty of simulation on the cleavage of chemical bonds. In this work, the co-micellization behavior, drug distribution regularities and dual pH/reduction-responsive drug release process of mixed micelles formed by disulfide-linked polycaprolactone-b-polyethylene glycol methyl ether methacrylate (PCL-SS-PPEGMA) and poly(ethylene glycol) methyl ether-b-poly(N,N-diethylamino ethyl methacrylate) (PDEA-PPEGMA) were studied by dissipative particle dynamics (DPD) mesoscopic simulations. A dedicated bond-breaking script was employed to accomplish the disulfide bond-breaking simulations. The results showed that PCL55-SS-PPEGMA10 and PDEA34-PPEGMA11 could be well mixed to form superior DOX-loaded micelles with good drug-loading capacity and drug-controlled release performance. To prepare the DOX-loaded micelles with optimized properties, the simulation results suggested the feed ratio of DOX:PCL55-SS-PPEGMA10:PDEA34-PPEGMA11 set to 3:4:4. Compared with the two single stimuli-response, the dual pH/reduction-response process perfectly combined both pH-response and reduction-response together, providing a higher release rate of DOX. Therefore, this study provides theoretical guidance aimed at the property optimization and micellar structure design of the dual pH/reduction-responsive mixed micelles.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Metacrilatos/química , Simulação de Dinâmica Molecular , Poliésteres/química , Polietilenoglicóis/química , Portadores de Fármacos/química , Concentração de Íons de Hidrogênio , Micelas , Estrutura Molecular , Oxirredução
4.
Rinsho Ketsueki ; 62(8): 1102-1111, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497197

RESUMO

Four cycles of ABVD followed by 30 Gy IFRT (ISRT) is a standard regimen, as an initial treatment, for patients with early-stage classical Hodgkin lymphoma (cHL), whereas 2 cycles of ABVD followed by 20 Gy IFRT (ISRT) is an alternative regimen for those with favorable early-stage cHL. For patients with unfavorable early-stage cHL including bulky disease, local radiotherapy can be safely omitted if negative findings on interim PET are obtained after 2 cycles of escalated BEACOPP plus 2 cycles of ABVD. ABVD (6/8 cycles) or brentuximab vedotin (BV) with concurrent AVD (6 cycles) is a standard regimen for patients with advanced-stage cHL. For elderly cHL patients (60 years of age or older) and multiple comorbidities, the risk of treatment-related adverse events is higher, which can potentially lead to poor outcomes. BV with sequential AVD therapy, which is a unique combination strategy, has been developed for elderly cHL patients. The combination of anti-PD-1 antibodies with AVD therapies is currently being evaluated in some clinical trials. This review includes current evidence that primarily focuses on randomized clinical trials for newly diagnosed adult cHL patients and management points in clinical practice for those patients.


Assuntos
Doença de Hodgkin , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/uso terapêutico , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Estadiamento de Neoplasias , Vimblastina/uso terapêutico
5.
Nanoscale ; 13(32): 13907, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34477666

RESUMO

Correction for 'Combining PD-L1 inhibitors with immunogenic cell death triggered by chemo-photothermal therapy via a thermosensitive liposome system to stimulate tumor-specific immunological response' by Jie Yu et al., Nanoscale, 2021, DOI: .


Assuntos
Lipossomos , Neoplasias , Doxorrubicina , Humanos , Inibidores de Checkpoint Imunológico , Morte Celular Imunogênica , Neoplasias/tratamento farmacológico , Terapia Fototérmica
6.
Nanoscale ; 13(31): 13375-13389, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34477743

RESUMO

Owing to its aggressive biological behavior, the lack of specific targets, and the strong therapeutic resistance of triple negative breast cancer (TNBC), current therapeutic strategies are still limited. The combination of multiple treatments has been confirmed as a promising strategy for TNBC therapy. However, the efficacy of combination therapy can be restricted due to increasing therapeutic resistance to various treatments. Herein, we constructed a nanodiamond (ND)-based nanoplatform for augmented mild-temperature photothermal/chemo combination therapy against TNBC, weakening the therapeutic resistance via autophagy inhibition enabled by the NDs. A layer-by-layer self-assembly approach was utilized to construct the ND-based nanoplatform. First, the NDs were modified with protamine sulphate (PS). Meanwhile, the photosensitizer indocyanine green (ICG) and the HSP70 small molecule inhibitor apoptozole (APZ) could be synchronously incorporated to form positively charged PS@ND (ICG + APZ). Then negatively charged hyaluronic acid (HA) was assembled onto the outer face of PS@ND (ICG + APZ) to form the NPIAs. Finally, the positively charged small molecule anti-cancer drug doxorubicin (DOX) could be adsorbed onto the surface of the NPIAs through electrostatic interactions (NPIADs). The resulting NPIADs could be triggered by NIR laser irradiation to exhibit enhanced mild-temperature photothermal therapy (PTT) effects via suppressing the expression of HSP70, and PTT combined with chemotherapy could further enhance the anti-tumor efficacy. Subsequently, the sensitivity of MDA-MB-231 cells could be significantly improved through the weakening of the thermal/drug resistance via autophagy inhibition, leading to augmented combination therapy that is efficient both in vitro and in vivo. Furthermore, the NPIADs could be used as a theranostic nanoplatform for fluorescence (FL) and photoacoustic (PA) imaging. Taken together, this study demonstrated a multifunctional ND-based nanoplatform for FL/PA imaging-guided augmented mild-temperature photothermal/chemo combination therapy via an autophagy regulation strategy against TNBC.


Assuntos
Hipertermia Induzida , Nanodiamantes , Nanopartículas , Neoplasias de Mama Triplo Negativas , Autofagia , Doxorrubicina/farmacologia , Humanos , Fototerapia , Temperatura , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
7.
Nanoscale ; 13(30): 13000-13013, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477783

RESUMO

Inorganic nanoparticles are gaining increasing attention as drug carriers because they respond to external physical stimuli, allowing therapy to be combined with diagnosis. Their drawback is low drug loading capacity, which can be improved by proper and efficacious functionalization. In this computational study, we take TiO2 spherical nanoparticles as prototype photoresponsive inorganic nanoparticles and we fully decorate them with two different types of bifunctional ligands: TETTs and DOPACs, which present different surface anchoring groups (silanol or catechol) but the same drug tethering COOH group, although in different concentrations (3 vs. 1), thus causing different steric hindrances. Then, we put these two types of nanocarriers in bulk water and in the presence of several DOX molecules and let the systems evolve through molecular dynamics (MD) simulations, clearly observing drug loading on the nanocarriers. This comparative MD study allows the investigation of the loading mechanism, performance of a conformational analysis and establishment of the guiding interactions through an energy decomposition analysis. We learn that DOX mostly interacts with the functionalized NPs through electrostatics, as a consequence of the protonated amino group, although several H-bonds are also established both with the ligands and with the oxide surface. Different ligands induce a different electrostatic potential around the NP; therefore, those which lead to the formation of more negative hotspots (here TETTs) are found to favour DOX binding. The leading role of electrostatics can provide a rational explanation for a pH-dependent drug release mechanism that is often invoked for DOX when reaching diseased cells because under anomalous acidic conditions both the NP surface and the carboxylate groups of the ligands are expected to get protonated, which of course would weaken, if not totally quench, the interaction of the nanocarrier with protonated DOX.


Assuntos
Doxorrubicina , Nanopartículas , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular
8.
Nanoscale ; 13(34): 14417-14425, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473184

RESUMO

The recurrence and metastasis of tumor after surgery is the main cause of death for patients with breast cancer. Systemic chemotherapy suffered from low delivery efficiency to tumors and the side effects of chemo drugs. Localized chemotherapy using drug-containing implants is an alternative, while the reconstruction of breast tissue is generally considered after chemotherapy, resulting in a second surgery for patients. Here, we describe a strategy using implantable drug-containing polymeric scaffolds to deliver chemo drugs directly to the post-resection site, and simultaneously provide mechanical support and regenerative niche for breast tissue reconstruction. When doxorubicin was loaded in mesoporous silica nanoparticles and subsequently incorporated into polycaprolactone scaffolds (DMSN@PCL), a 9-week sustained drug release was achieved post implantation in mice. The local recurrence of residual tumor after surgery was significantly inhibited within 4 weeks in a post-surgical mouse model bearing xenograft MDA-MB-231 tumor. DMSN@PCL scaffolds exhibited good biocompatibility in mice during the treatment. We believe our strategy holds great promise as an adjuvant localized chemotherapy in clinics for combating post-resection breast cancer recurrence.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Feminino , Humanos , Camundongos , Poliésteres
9.
Mater Sci Eng C Mater Biol Appl ; 128: 112311, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474862

RESUMO

Herein, we design a rGO-based magnetic nanocomposite by decorating rGO with citrate-coated magnetic nanoparticles (CMNP). The magnetic rGO (mrGO) was modified by phospholipid-polyethylene glycol to prepare PEGylated mrGO, for conjugating with gastrin-releasing peptide receptor (GRPR)-binding peptide (mrGOG). The anticancer drug doxorubicin (DOX) was bound to mrGO (mrGOG) by π-π stacking for drug delivery triggered by the low pH value in the endosome. The mrGOG showed enhanced photothermal effect under NIR irradiation, endorsing its role for dual targeted DOX delivery. With efficient DOX release in the endosomal environment and heat generation from light absorption in the NIR range, mrGOG/DOX could be used for combination chemo-photothermal therapy after intracellular uptake by cancer cells. We characterized the physico-chemical as well as biological properties of the synthesized nanocomposites. The mrGOG is stable in biological buffer solution, showing high biocompatibility and minimum hemolytic properties. Using U87 glioblastoma cells, we confirmed the magnetic drug targeting effect in vitro for selective cancer cell killing. The peptide ligand-mediated targeted delivery increases the efficiency of intracellular uptake of both nanocomposite and DOX up to ~3 times due to the over-expressed GRPR on U87 surface, leading to higher cytotoxicity. The increased cytotoxicity using mrGOG over mrGO was shown from a decreased IC50 value (0.70 to 0.48 µg/mL) and an increased cell apoptosis rate (19.8% to 47.1%). The IC50 and apoptosis rate changed further to 0.19 µg/mL and 76.8% in combination with NIR laser irradiation, with the photothermal effect supported from upregulation of heat shock protein HSP70 expression. Using U87 tumor xenograft model created in nude mice, we demonstrated that magnetic guidance after intravenous delivery of mrGOG/DOX could significantly reduce tumor size and prolong animal survival over free DOX and non-magnetic guided groups. Augmented with NIR laser treatment for 5 min, the anti-cancer efficacy significantly improves with elevated cell apoptosis and reduced cell proliferation. Together with safety profiles from hematological as well as major organ histological analysis of treated animals, the mrGOG nanocomposite is an effective nanomaterial for combination chemo-photothermal cancer therapy.


Assuntos
Hipertermia Induzida , Nanocompostos , Neoplasias , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Grafite , Fenômenos Magnéticos , Camundongos , Camundongos Nus , Fototerapia , Receptores da Bombesina
10.
Mater Sci Eng C Mater Biol Appl ; 128: 112317, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474868

RESUMO

Acid-triggered degradable polyprodrug P(DOX-AH) was designed for long-acting drug delivery with minimal leakage and enhanced antitumor efficacy. By facile polymerization of doxorubicin (DOX) and N-(tert-butoxycarbonyl)acryloylhydrazine (Boc-AH), P(DOX-AH) with drug as unique repeating unit was obtained, possessing an ultrahigh drug content. It was stable in the neutral media but could degrade completely into DOX-AH in the acidic media without any other by-product. The cleavage of the hydrazone linkage between the DOX-AH repeating units was revealed by the LC-MS/MS analysis. Furthermore, a slow solubility-controlled drug release performance was achieved in the acidic media because of the low solubility of the released DOX-AH. Even with the slow DOX-AH releasing, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments. These features demonstrated the promising potential of the proposed polyprodrug for long-acting drug delivery in future tumor chemotherapy.


Assuntos
Polímeros , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas
11.
Langmuir ; 37(38): 11222-11232, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34524822

RESUMO

Efficient delivery of therapeutic compounds to their sites of action has been a ubiquitous concern throughout the history of human medicine. The tumor microenvironment offers a variety of endogenous stimuli that may be exploited by a responsive nanocarrier, including heterogeneities in redox potential. In the early stages of the design of such responsive delivery systems, it is necessary to develop a comprehensive understanding of the biophysical mechanism by which the stimulus response occurs, as well as how the response may change from the inclusion of cargo compounds. We describe the optimization of lipid compositions for liposomes containing synthetic ferrocene-appended lipids to achieve highly efficient loading of doxorubicin via an ethylenediaminetetraacetic acid (EDTA) gradient. Liposomes containing ferrocenylated phospholipid are shown to be unstable to the loading conditions, while those including a ferrocenylated alkylammonium amphiphile obtain a near-quantitative loading efficiency. Calorimetric studies demonstrate that this instability is the consequence of the relative degree of lipid hydrolysis that occurs under the acidic loading conditions. Drug-loaded liposomes of the optimized composition are studied by cryo-TEM; the presence of doxorubicin aggregates is observed inside vesicles, and doxorubicin release, as well as the changes in membrane structure resulting from oxidant treatment, is also observed by cryogenic transmission electron microscopy (cryo-TEM). These results further demonstrate the potential of ferrocene lipids in the design of redox-responsive nanocarriers and begin to explore their possible role as probes of membrane dynamics.


Assuntos
Doxorrubicina , Lipossomos , Sistemas de Liberação de Medicamentos , Ácido Edético , Humanos , Lipídeos , Metalocenos
12.
Biomater Sci ; 9(19): 6501-6509, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34582538

RESUMO

Recently, hypothermal photothermal therapy (HPTT) seemed essential for the future clinical transformation of cancer optical therapies. However, at a lower working temperature, heat shock proteins (HSPs) seriously affect the anti-tumor effect of HPTT. This work reports a reasonable design of a dual-responsive nanoplatform for the synergistic treatment of chemotherapy and HPTT. We adopted a one-step method to wrap indocyanine green (ICG) into imidazole skeleton-8 (ZIF-8) and further loaded it with the chemotherapy drug doxorubicin (DOX). Furthermore, we introduced Hsp-70 siRNA to block the affection of HSPs at an upstream node, thereby avoiding the side effects of traditional heat shock protein inhibitors. The prepared ZIF-8@ICG@DOX@siRNA nanoparticles (ZID-Si NPs) could significantly improve the stability of siRNA to effectively down-regulate the expression of HSP70 protein during the photothermal therapy, thus realizing the pH-controlled and NIR-triggered release of the chemotherapeutical drug DOX. Moreover, tumors were also imaged accurately by ICG wrapped in ZID-Si nanoparticles. After the evaluation of the in vitro and in vivo photothermal effect as well as the anti-tumor activity, we found that the added Hsp-70 siRNA enhanced the synergistic anti-cancer activity of HPTT and chemotherapy. In summary, this work holds great potential in cancer treatment, and suggests better efficacy of synergistic chemo/HPTT than the single-agent therapy.


Assuntos
Hipertermia Induzida , Nanopartículas , Doxorrubicina , Liberação Controlada de Fármacos , Verde de Indocianina , Terapia Fototérmica , RNA Interferente Pequeno/genética
13.
Biomater Sci ; 9(19): 6609-6622, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34582539

RESUMO

Mitochondria are reported to play a paramount role in tumorigenesis which positions them as an instrumental druggable target. However, selective drug delivery to cancer-localized mitochondria remains challenging. Herein, we report for the first time, the design, development and evaluation of a hepatic cancer-specific mitochondria-targeted dual ligated nanoscale metal-organic framework (NMOF) for cellular and mitochondrial sequential drug delivery. Surface functionalization was performed through covalent-linking of folic acid and triphenylphosphonium moieties to the aminated Zr-based MOF, NH2-UiO-66. The characterization of the dual-ligated NMOFs using XRD, FTIR, DSC and BET analysis proved the successful conjugation process. Assessment of the drug loading and release profiling of doxorubicin (DOX)-loaded NMOF confirmed the proper retention of the drug within the NMOF porous structure alongside enhanced release in the tumor acidic environment. Furthermore, biological evaluation of the anti-tumor activity of the DOX-loaded dual-ligated NMOF on hepatocellular carcinoma affirmed the superiority of the developed system in killing the cancerous cells via apoptosis induction and halting cell cycle progression. This study attempts to underscore the promising potential of surface functionalized NMOFs in developing anticancer drug delivery systems to achieve targeted therapy.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Estruturas Metalorgânicas , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Mitocôndrias
14.
Int J Pharm ; 608: 121066, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34481009

RESUMO

Doxorubicin (DOX) is one of the most commonly used and effective chemotherapy drugs among anthracyclines. An inherent limitation of DOX is its nonspecificity, which can cause serious side effects, thereby preventing the therapeutic use of high drug doses. In this study, we designed and created a simple nano-drug delivery system (PEG-MAF = P) with low biological toxicity that was responsive to the tumor environment. PEG-MAF = P was designed to self-assemble into nanospheres via control of a phenylalanine dipeptide (FF). The N-terminus of the peptide was linked to aldehyde groups at both ends of oxidized Pluronic F127 (F127-CHO) via Schiff bonds. The acidic environment surrounding the tumors was suitable for triggering the Schiff bonds, causing the nanospheres to disintegrate. The C-terminus of FF was connected to a ligand peptide, ATN-161, which was able to recognize cells expressing high levels of integrin α5ß1 antigens both in vivo and in vitro. To prevent the impediment in drug release, PEG was linked via a matrix metalloproteinase-9 response peptide. Therefore, in an acidic tumor microenvironment containing MMP-9, PEG-MAF = P disintegrated and rapidly released the drug. PEG-MAF = P exhibited low cytotoxicity, high drug-loading rate, and excellent antitumor properties both in vivo and in vitro. Compared with free DOX, PEG-MAF = P-DOX reduced injury to normal tissues.


Assuntos
Portadores de Fármacos , Microambiente Tumoral , Antibióticos Antineoplásicos , Linhagem Celular Tumoral , Doxorrubicina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Polietilenoglicóis
15.
Int J Pharm ; 608: 121073, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34481887

RESUMO

A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in vitro drug release represents an important critical quality attribute involved in pharmacokinetics. Establishing in vitro-in vivo relationships for nanomedicines requires a careful analysis of the clinical data with respect to the unique differences between drugs and nanomedicines. Also, the biorelevant assay must reflect the release mechanism of the carrier. Four drug delivery systems of doxorubicin were evaluated for their in vitro release behavior under biorelevant conditions using the dispersion releaser. The pharmacokinetics observed during the first-in-men clinical trials were analyzed using a custom-made physiologically-based nanocarrier biopharmaceutics model. The drug product Lipodox® and the clinical candidate NanoCore-7.4 were evaluated to validate the model. Afterward, the in vivo performances of the preclinical candidates NanoCore-6.4 and doxorubicin-loaded nano-cellular vesicle technology systems (an extracellular vesicle preparation) were predicted. In vitro and in vivo release were in good correlation as indicated by the coefficients of determination of 0.98648 (NanoCore-7.4) and 0.94107 (Lipodox®). The predictions required an estimation of the carrier half-life in blood circulation leading to considerable uncertainty. Still, the simulations narrow down the possible scenarios in the clinical evaluation of nanomedicines and provide a valuable addition to animal studies.


Assuntos
Doxorrubicina , Preparações Farmacêuticas , Animais , Biofarmácia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos
16.
Int J Pharm ; 608: 121077, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34487811

RESUMO

Cancer metastasis, which increases the mortality in a short period of time, has been considered as the main challenge in tumor treatment. However, tumor growth suppression also should not be ignored in cancer metastasis treatment. Recently, accumulating evidences have suggested that mitochondria play an important role in mitigating caner metastasis. Nucleus, as the repository of genetic information, plays a key role in cell proliferation. However, it remains elusive that the concurrent impairment of nucleus and mitochondria may achieve better anti-tumor and anti-metastatic effects. Here, we designed a mitochondria-penetrating peptide modified doxorubicin (MPP-Dox) loaded N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugates (PM), as well as a nuclear accumulating HPMA copolymer Dox conjugates (PN) by the nuclear tendency of Dox. After co-delivering the two copolymers (abbreviation for PMN), PM promoted cell apoptosis and inhibited tumor metastasis by damaging mitochondria, whereas PN suppressed cell proliferation and promoted apoptosis by destroying nucleus. Importantly, PM and PN complemented each other as expected. The mitochondrial dysfunction and tumor metastasis inhibition of PM was improved by PN, while cell proliferation suppression and apoptosis by nucleus destroying of PN was enhanced by PM. As a result, tumor growth of breast cancer 4T1 cells in vivo was significantly restrained and lung metastasis was potently decreased and almost eradicated, fully reflecting the advantages of organelle targeting combination therapy. As a consequence, our work showed that concurrent impairment of nucleus and mitochondria was feasible and beneficial to metastatic cancer treatment.


Assuntos
Doxorrubicina , Neoplasias , Apoptose , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Mitocôndrias , Polímeros
17.
Nat Commun ; 12(1): 5270, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489413

RESUMO

Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.


Assuntos
Coração/fisiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Fator 1 Relacionado a NF-E2/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Doxorrubicina/farmacologia , Feminino , Heme Oxigenase (Desciclizante)/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Masculino , Camundongos Knockout , Camundongos Transgênicos , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/fisiologia , Fator 1 Relacionado a NF-E2/genética , Oxirredução , Proteostase , Ratos Sprague-Dawley , Regeneração
18.
J Biomed Nanotechnol ; 17(8): 1554-1563, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544533

RESUMO

Clinical treatment of triple negative breast cancer (TNBC) is very poor for lack of effective treatment combination selection. Protein C receptor (PROCR) is a novel cancer stem marker in TNBC patients tumor tissues. Developed based on peptide BP10 with affinity to PROCR as a targeting element, constructing a peptide drug conjugate of BP10 covalently coupling doxorubicin with disulfide bonds. This study demonstrated that the constructed BP10-DOX can selectively target Triplenegative breast cancer cells expressing PROCR and controlled release of DOX in response to the GSH environment. Moreover, BP10-DOX improves the therapeutic efficiency on MDA-MB-231 cells in vitro. Further evidence obtained from in vivo xenograft experiments revealed that administration of BP10-DOX enhanced the antitumor efficacy. This study developed a promising chemotherapy strategy for TNBC.


Assuntos
Preparações Farmacêuticas , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Peptídeos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
19.
Mater Sci Eng C Mater Biol Appl ; 129: 112389, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34579908

RESUMO

Nanocarriers have been widely employed to deliver chemotherapeutic drugs for cancer treatment. However, the insufficient accumulation of nanoparticles in tumors is an important reason for the poor efficacy of nanodrugs. In this study, a novel drug delivery system with a self-assembled amphiphilic peptide was designed to respond specifically to alkaline phosphatase (ALP), a protease overexpressed in cancer cells. The amphiphilic peptide self-assembled into spherical and fibrous nanostructures, and it easily assembled into spherical drug-loaded peptide nanoparticles after loading of a hydrophobic chemotherapeutic drug. The cytotoxicity of the drug carriers was enhanced against tumor cells over time. These spherical nanoparticles transformed into nanofibers under the induction of ALP, leading to efficient release of the encapsulated drug. This drug delivery strategy relying on responsiveness to an enzyme present in the tumor microenvironment can enhance local drug accumulation at the tumor site. The results of live animal imaging showed that the residence time of the morphologically transformable drug-loaded peptide nanoparticles at the tumor site was prolonged in vivo, confirming their potential use in antitumor therapy. These findings can contribute to a better understanding of the influence of drug carrier morphology on intracellular retention.


Assuntos
Antineoplásicos , Nanopartículas , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos
20.
Integr Cancer Ther ; 20: 15347354211035450, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34490824

RESUMO

Doxorubicin (Dox) induces senescence in numerous cancer cell types, but these senescent cancer cells relapse again if they are not eliminated. On this principle, we investigated the apoptotic effect of thymoquinone (TQ), the active ingredient of Nigella sativa seeds and costunolide (COS), the active ingredient of Costus speciosus, on the senescent colon (Sen-HCT116) and senescent breast (Sen-MCF7) cancer cell lines in reference to their corresponding proliferative cells to rapidly eliminate the senescent cancer cells. The senescence markers of Sen-HCT116 and Sen-MCF7 were determined by a significant decrease in bromodeoxyuridine (BrdU) incorporation and significant increases in SA-ß-gal, p53, and p21 levels. Then proliferative, Sen-HCT116, and Sen-MCF7 cells were subjected to either TQ (50 µM) or COS (30 µM), the Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), caspase 3 mRNA expression and its activity were established. Results revealed that TQ significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ, MCF7 + TQ, and MCF7 + Dox5 + TQ compared with their corresponding controls. COS significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ and MCF7 + Dox5 + TQ compared with their related controls. Also, TQ and COS were significantly increased caspase 3 activity and cell proliferation of Sen-HCT116 and Sen-MCF7. The data revealed a higher sensitivity of senescent cells to TQ or COS than their corresponding proliferative cells.


Assuntos
Apoptose , Recidiva Local de Neoplasia , Benzoquinonas , Colo , Doxorrubicina/farmacologia , Humanos , Sesquiterpenos
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