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1.
Orv Hetil ; 161(11): 425-433, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32148096

RESUMO

Introduction: Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The best survival rates are expected after surgical removal, thus the aim of a complex treatment is to achieve resecability in locally and locoregionally advanced disease. Aim: The primary purpose of this study was to evaluate if the neoadjuvant systemic treatment leads to better overall survival compared to irradiation solely. Method: From January 2015 to December 2018, we enrolled 28 patients diagnosed with irresecable, locally and locoregionally advanced high-risk endometrial carcinoma. Patients were treated by neoadjuvant paclitaxel-carboplatin, then radical hysterectomy, bilateral oophorectomy and lymphadenectomy were performed. Results: After administration of 6 cycles of carboplatin-paclitaxel, the control MR test showed tumor shrinkage in all patients. Complete resection was achieved in the case of every patient. Tumor residuum in lymph nodes was verified in 4 cases by pathological evaluation. The 2-year survival and the 2-year progression-free survival rates were 65,1% and 66,1%, respectively. The median overall survival was 16,5 months. Conclusion: Neoadjuvant treatment can be an effective approach in providing the conditions for complete tumor resection, which may result in survival advantage. Despite multimodal treatment, prognosis is poor. Orv Hetil. 2020; 161(11): 425-433.


Assuntos
Carboplatina/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/cirurgia , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino/uso terapêutico , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Excisão de Linfonodo , Estadiamento de Neoplasias , Ovariectomia , Taxa de Sobrevida , Resultado do Tratamento
2.
Radiol Med ; 125(2): 165-176, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31605354

RESUMO

AIMS: The aim of the study was to predict and assess treatment response by histogram analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to patients with locally advanced esophageal squamous cell carcinoma receiving chemoradiotherapy (CRT). MATERIALS AND METHODS: Seventy-two patients with locally advanced esophageal squamous cell carcinoma who underwent DCE-MRI before and after chemoradiotherapy were enrolled and divided into the complete response (CR) group and the non-CR group based on RECIST. The histogram parameters (10th percentile, 90th percentile, median, mean, standard deviation, skewness, and kurtosis) of pre-CRT and post-CRT were compared using a paired Student's t test in the CR and non-CR groups, respectively. The histogram parameter differences between the CR and the non-CR groups were compared using an unpaired Student's t test. A receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance. RESULTS: The histogram parameters of Ktrans values were observed to have significantly decreased after chemoradiotherapy in the CR group. The CR responders showed significantly higher median, mean, and 10th and 90th percentile of pre-Ktrans values than those of the non-CR group. The histogram analysis indicated the decreased heterogeneity in the CR group after CRT. Esophageal cancer with higher pre-Ktrans and lower post-Ktrans values indicated a good treatment response to CRT. Pre-Ktrans-10th showed the best diagnostic performance in predicting the chemoradiotherapy response. CONCLUSIONS: The histogram parameters of Ktrans are useful in the assessment and prediction of the chemoradiotherapy response in patients with advanced esophageal squamous cell carcinoma. DCE-MRI could serve as an adjunctive imaging technique for treatment planning.


Assuntos
Quimiorradioterapia/métodos , Carcinoma de Células Escamosas do Esôfago/diagnóstico por imagem , Carcinoma de Células Escamosas do Esôfago/terapia , Imagem por Ressonância Magnética/métodos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Dosagem Radioterapêutica , Estudos Retrospectivos
3.
Clin Nucl Med ; 45(2): 127-128, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31876811

RESUMO

Paclitaxel-ramucirumab chemotherapy is indicated in second line of metastatic gastroesophageal junction cancer (mGEJC) after progression under platinum-5-FU chemotherapy. Nevertheless, the reported common response after treatment is only partial within series. To date, only 1 case report of negative posttreatment FDG PET/CT was published without baseline examination from RAINBOW trial. We illustrated the interest of FDG PET/CT to evaluate treatment especially paclitaxel-ramucirumab with 2 examples of complete metabolic responses in 2 patients having different HER2 biomarker profiles of mGEJC. As illustrated, FDG PET/CT emerges as a useful approach for therapeutic assessment of targeted drugs in mGEJC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/diagnóstico por imagem , Fluordesoxiglucose F18 , Paclitaxel/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico
4.
Int J Nanomedicine ; 14: 8543-8560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802868

RESUMO

Background: Nanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1. Materials and methods: To improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD. Results: Compared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent. Conclusion: Our findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Oligopeptídeos/administração & dosagem , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Invasividade Neoplásica , Oligopeptídeos/química , Paclitaxel/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Distribuição Tecidual
5.
Int J Nanomedicine ; 14: 9453-9467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819443

RESUMO

Background: Ovarian cancer is a common malignancy in the female reproductive system with a high mortality rate. The most important reason is multidrug resistance (MDR) of cancer chemotherapy. To reduce side effects, reverse resistance and improve efficacy for the treatment of ovarian cancer, a "core-shell" polymeric nanoparticle-mediated curcumin and paclitaxel co-delivery platform was designed. Methods: Nuclear magnetic resonance confirmed the successful grafting of polyethylenimine (PEI) and stearic acid (SA) (PEI-SA), which is designed as a mother core for transport carrier. Then, PEI-SA was modified with hyaluronic acid (HA) and physicochemical properties were examined. To understand the regulatory mechanism of resistance and measure the anti-tumor efficacy of the treatments, cytotoxicity assay, cellular uptake, P-glycoprotein (P-gp) expression and migration experiment of ovarian cancer cells were performed. In addition, adverse reactions of nanoformulation to the reproductive system were examined. Results: HA-modified drug-loaded PEI-SA had a narrow size of about 189 nm in diameters, and the particle size was suitable for endocytosis. The nanocarrier could target specifically to CD44 receptor on the ovarian cancer cell membrane. Co-delivery of curcumin and paclitaxel by the nanocarriers exerts synergistic anti-ovarian cancer effects on chemosensitive human ovarian cancer cells (SKOV3) and multi-drug resistant variant (SKOV3-TR30) in vitro, and it also shows a good anti-tumor effect in ovarian tumor-bearing nude mice. The mechanism of reversing drug resistance may be that the nanoparticles inhibit the efflux of P-gp, inhibit the migration of tumor cells, and curcumin synergistically reverses the resistance of PTX to increase antitumor activity. It is worth noting that the treatment did not cause significant toxicity to the uterus and ovaries with the observation of macroscopic and microscopic. Conclusion: This special structure of targeting nanoparticles co-delivery with the curcumin and paclitaxel can increase the anti-tumor efficacy without increasing the adverse reactions as a promising strategy for therapy ovarian cancer.


Assuntos
Curcumina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Polímeros/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Curcumina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Ácido Hialurônico/química , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Polietilenoimina/química , Ácidos Esteáricos/química , Distribuição Tecidual , Resultado do Tratamento
6.
Int J Nanomedicine ; 14: 7339-7352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686810

RESUMO

Purpose: To deliver the chemotherapeutics through the nanoparticles, the delivery system should accumulate at the tumor site first and then penetrate through the interstitium into the interior. The specific tumor-targeting pathway mediated via the receptor-ligand binding could achieve the desirable accumulation of nanoparticles, and the nanoparticles with smaller sizes were required for penetration. Methods and materials: We constructed a size-shrinkable nanocluster modified with a tumor-targeting motif IF-7 (IF-7-MNC) based on a pH-sensitive framework which could be disintegrated in an acid environment to release the micelles aggregated inside. The micelles were constructed by amphiphilic block copolymers PEG-PLA to encapsulate paclitaxel (PTX), while the cross-linked framework consisting of TPGS-PEI was used as a net to gather and release micelles. This nanoplatform could specifically bind with the tumor receptor Annexin A1 through the ligand IF-7 and then shrunk into small micelles with a desirable size for penetration. Conclusion: IF-7-MNC of 112.27±6.81 nm could shrink into micelles in PBS (0.01 M, pH 5.0) with sizes of 14.89±0.32 nm. The cellular-uptake results showed that IF-7-MNC could be significantly internalized by A549 cells and HUVEC cells, while the penetration of IF-7-MNC could be more prominent into the 3D-tumor spheroids compared with that of MNC. The biodistribution results displayed that the fluorescence of IF-7-MNC in the tumor site at 24 hrs was 4.5-fold stronger than that of MNC. The results of anti-tumor growth demonstrated that IF-7-MNC was more favorable for the tumor therapy than MNC, where the inhibitory rate of tumor growth was 88.29% in the PTX-loaded IF-7-MNC (IF-7-PMNC) treated group, significantly greater than PMNC treatment group (p<0.05).


Assuntos
Antineoplásicos/farmacologia , Carboidratos/química , Sistemas de Liberação de Medicamentos , Micelas , Nanopartículas/química , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Peptídeos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polietilenoglicóis , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Eletricidade Estática , Distribuição Tecidual
7.
Int J Nanomedicine ; 14: 7431-7446, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686815

RESUMO

Background: Low density lipoprotein (LDL) has been regarded as a promising antitumor drug vehicle. However some problems, such as rare source, difficulty of large-scale production, and potential safety concerns, hinder its clinical application. Purpose: The objective of this study is to develop a biomimetic LDL nanocarrier by replacing the native apolipoprotein B-100 (apoB-100) with an artificial amphipathic peptide and demonstrate its antitumor efficacy. Methods: The amphipathic hybrid peptide (termed as FPL) consisting of a lipid binding motif of apoB-100 (LBMapoB)-polyethylene glycol (PEG)-folic acid (FA) was synthesized and characterized by 1H NMR and circular dichroism. FPL decorated lipoprotein-mimic nanoparticles (termed as FPLM NPs) were prepared by a modified solvent emulsification method. Paclitaxel (PTX) was incorporated into NPs and its content was quantified by HPLC analysis. The morphology of NPs was observed by transmission electron microscopy (TEM), and the particle size and zeta potential of NPs were determined by dynamic light scattering (DLS). The colloidal stability of FPLM NPs was evaluated in PBS containing bovine serum albumin (BSA). In vitro release of PTX loaded FPLM NPs was evaluated using the dialysis method. Cellular uptake and cytotoxity assayswere evaluated on human cervical cancer cells (HeLa) and lung cancer cells (A549). Tumor inhibition in vivo was investigated in M109 tumor-bearing mice via tail vein injection of Taxol formulation and PTX loaded NPs. Results: The composition of FPLM NPs, including cholesteryl oleate, glyceryl trioleate, cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and FPL peptides, was optimized to be 5:1:1:3:10 (w/w). FPLM NPs had a spherical shape with a mean diameter of 83 nm and a negative charge (-12 mV). FPLM NPs with optimum formulation had good colloidal stability in BSA solution.The release of PTX from FPLM NPs was slow and sustained. The uptake of FPLM NPs was higher in folate receptor (FR) overexpressing tumor cells (HeLa cells) than in FR deficient tumor cells (A549 cells). The intracellular distribution indicated that FPLM NPs had the lysosome escape capacity. The internalization mechanism of FPLM NPs was involved with clathrin- and caveolae-mediated endocytosis and FR played a positive role in the internalization of FPLM NPs. The CCK-8 assay demonstrated that FPLM NPs exhibited notably better anti-tumor effect than Taxol formulation in vitro. Moreover, PTX loaded FPLM NPs produced very marked anti-tumor efficiency in M109 tumor-bearing mice in vivo. Conclusion: FPLM NPs is a promising nanocarrier which can improve the therapeutic effect and reduce the side effects of antitumor drugs.


Assuntos
Materiais Biomiméticos/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Lipoproteínas LDL/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Peptídeos/química , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apolipoproteína B-100/química , Coloides/química , Liberação Controlada de Fármacos , Endocitose , Ácido Fólico/química , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Paclitaxel/farmacologia , Tamanho da Partícula , Polietilenoglicóis/química , Eletricidade Estática
8.
Braz J Med Biol Res ; 52(11): e8657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664305

RESUMO

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Neoplasias da Mama/metabolismo , Proteína HMGB1/metabolismo , Células MCF-7/metabolismo , MicroRNAs/metabolismo , Paclitaxel/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , MicroRNAs/genética , Paclitaxel/uso terapêutico , Regulação para Cima/genética
9.
Anticancer Res ; 39(10): 5565-5572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570451

RESUMO

BACKGROUND/AIM: The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). RESULTS: CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. CONCLUSION: There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/uso terapêutico , Fibroblastos Associados a Câncer/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Ácido Oxônico/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Tegafur/uso terapêutico
10.
BMC Cancer ; 19(1): 941, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604467

RESUMO

BACKGROUND: Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting. METHODS: This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0-2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study. DISCUSSION: The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Oxaliplatina/uso terapêutico , Paclitaxel/uso terapêutico , Doenças do Sistema Nervoso Periférico/epidemiologia , Neoplasias Gástricas/tratamento farmacológico , Administração Intravenosa , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Relação Dose-Resposta a Droga , Seguimentos , Humanos , Japão , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Medidas de Resultados Relatados pelo Paciente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários
11.
Gan To Kagaku Ryoho ; 46(10): 1569-1572, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31631141

RESUMO

Nanoparticle albumin-bound paclitaxel(nab-PTX)is effective as second-line chemotherapy for advanced gastric cancer. Long-term administration is generally impossible because of peripheral sensory neuropathy. However, we report 2 cases that were treated with>35 cycles of nab-PTX with dose reduction to control disease progression, which appears to be the highest number cycles so far reported. Case 1 was a male patient in his 70s, with distant lymph node metastases and an advanced primary lesion(tub2). He received 6 cycles S-1/CDDP and achieved a partial response; however, the treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 36 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy. Case 2 was another male patient in his 70s, who underwent total gastrectomy for gastric cancer(mucinous adenocarcinoma). Virchow metastasis was detected 6months after surgery. He received 1 cycle S-1/CDDP and achieved a partial response; however, treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 41 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy.


Assuntos
Albuminas/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Gástricas , Idoso , Gastrectomia , Humanos , Masculino , Neoplasias Gástricas/terapia
12.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597361

RESUMO

Paclitaxel-lipoate (IDD-1040) is a conjugate formed by the chemical joining of the two compounds, by condensing a lipoic acid moiety to the C2' of paclitaxel. IDD-1040 was evaluated for its anti-tumor activity and potential druggability, using an in vivo non-small-cell, lung cancer (NSCLC) xenograft mouse model. In the in vivo studies, IDD-1040 showed a maximum tolerated dose (MTD) of 250 mg/kg compared to paclitaxel (PTX), with an MTD of 20 mg/kg. Most interesting, IDD-1040 demonstrated higher anti-tumor activity, and its inhibitory activity on tumor volume (cell growth) was dose-dependent. That anti-tumor activity persisted for two weeks after cessation of IDD-1040 treatment, as opposed to PTX cessation, after which the tumor relapsed, confirming that IDD-1040 exhibits superior tumor inhibition. Similar to PTX treatment, no marked body weight decrease was observed during IDD-1040 treatment, indicating a low toxicity profile. The increase in animal body weight noted over time was due to the increasing weight of tumors, recorded in all the mouse test groups. The results also showed that mortality rate of mice was reduced by treatment with IDD-1040, more so than with PTX. Furthermore, in a preliminary study on the ex vivo distribution of IDD-1040, neutropenia was primarily concentrated in the liver 1 h after injection, and most of the drug was metabolized by the liver in 24 h. All of these results demonstrate IDD-1040's great potential as a candidate drug for cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/química , Paclitaxel/farmacologia , Ácido Tióctico/química , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Paclitaxel/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Zhonghua Fu Chan Ke Za Zhi ; 54(9): 588-594, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31550774

RESUMO

Objective: To investigate the efficacy and side effect of paclitaxel liposome for neoadjuvant chemotherapy (NACT) in locally advanced cervical cancer. Methods: This study were included 265 cervical cancer patients staging Ⅰb2 and Ⅱa2 who underwent paclitaxel-platinum NACT followed by radical surgery from June 2008 to December 2016 in the Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences. All patients were classified into two groups with 106 patients in paclitaxel liposome group and 159 patients in traditional paclitaxel group. The difference in clinicopathologic characteristics, efficacy and side effect were analyzed retrospectively between the two groups. Results: (1) Clinicopathologic characteristics: there were no significant difference in clinicopathologic characteristics between the two groups, including age, body mass index, clinical stage, pathological histology, cycles of NACT, combined platinum regimen, lymph-vascular space invasion, lymph node metastasis, deep stromal invasion, and postoperative adjuvant therapy (all P>0.05). (2) Efficacy: after NACT, the overall response occurred in 90 (15 complete response plus 75 partial response) of 106 cases in the paclitaxel liposome group versus 131 (21 complete response plus 110 partial response) of 159 cases in the traditional paclitaxel group without statistical significance (84.9% vs 82.4%; χ(2)=0.291, P=0.590). A total of 248 patients received surgery after NACT and were evaluable in survival. The 5-year recurrence-free survival (RFS) rate and 5-year overall survival (OS) rate of these patients was 85.1% and 88.2%. The 5-year RFS rate in the paclitaxel liposome group was 85.9% compared with 85.2% in the traditional paclitaxel group, while the corresponding 5-year OS rate was 88.5% and 88.7%, respectively. There was no statistically significant difference in efficacy between the two groups (P=0.968, P=0.797). (3) Side effect: the incidence of allergic reaction between the paclitaxel liposome group and the traditional paclitaxel group was 0 versus 1.9% (3/159) without statistical significance (P=0.277). But the incidence of neurotoxicity in the paclitaxel liposome group significantly decreased compared with the traditional paclitaxel group (6.6% vs 15.7%, P<0.05), as well as the incidence of alopecia (67.9% vs 79.2%, P<0.05) and myalgia (17.9% vs 28.9%, P<0.05). However, significant differences were not found in terms of hematological toxicity, gastrointestinal reaction, and hepatic function damage (P>0.05). Conclusion: In paclitaxel-platinum NACT of local advanced cervical cancer, paclitaxel liposome can achieve similar efficacy compared with traditional paclitaxel, but paclitaxel liposome is helpful in decreasing the toxicity of neurotoxicity, alopecia and myalgia.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Quimioterapia Adjuvante/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Paclitaxel/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Lipossomos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
14.
Pathol Res Pract ; 215(10): 152606, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31500928

RESUMO

BACKGROUND: Extended from our previously observation that expression of miR-1307 in chemoresistant primary ovarian cancer tissues is elevated, here we are aiming to dissect the function of miR-1307 and its predicted target gene, CIC (capicua transcriptional repressor), in ovarian cancer chemotherapy. METHODS: We evaluated the expression of miR-1307 and CIC in chemoresistant and chemosensitive ovarian cancer tissues and cells by real time-PCR and western blot. We used chemoresistant/chemosensitive cells with miR-1307 suppression/overexpression to study the biological effects of miR-1307 by MTT and flow cytometer. Dual luciferase reporter gene assay was used to validate direct binding between miR-1307 and the 3'-UTR of CIC. Real-time PCR and western blot analyses, MTT and flow cytometry were used to reveal the biological effects of miR-1307 and CIC, as well as their regulation. RESULTS: We found that miR-1307 affects cell cycle dynamics, cell viability in ovarian cancer cells. In addition, its expression level can influence chemosensitivity to paclitaxel in ovarian cancer cells. We also validate that CIC is a downstream target of miR-1307 via its regulation on 3'-UTR of CIC gene and ETV4 and ETV5 are also regulated by miR-1307/CIC axis. CONCLUSIONS: Our data suggested that miR-1307 may be involved in the resistance of ovarian cancer to chemotherapy drugs via regulation of CIC, and should be further explored as a potential therapeutic target.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Proteínas Repressoras/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/uso terapêutico
15.
Mater Sci Eng C Mater Biol Appl ; 105: 110038, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546359

RESUMO

Ovarian cancer is the most lethal gynecological cancer of female reproductive system. In order to improve the survival rate, some modifications on nanoparticles surfaces have been investigated to promote active targeting of drugs into tumor microenvironment. The aim of this study was the development and characterization of folate-modified (PN-PCX-FA) and unmodified PLGA nanoparticles (PN-PCX) containing paclitaxel for ovarian cancer treatment. Nanocarriers were produced using nanoprecipitation technique and characterized by mean particle diameter (MPD), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FTIR, in vitro cytotoxicity and cellular uptake. PN-PCX and PN-PCX-FA showed MPD < 150 nm and PDI < 0.2 with high EE (about 90%). Cytotoxicity assays in SKOV-3 cells demonstrated the ability of both formulations to cause cellular damage. PCX encapsulated in PN-PCX-FA at 1 nM showed higher cytotoxicity than PN-PCX. Folate-modified nanoparticles showed a 3.6-fold higher cellular uptake than unmodified nanoparticles. PN-PCX-FA is a promising system to improve safety and efficacy of ovarian cancer treatment. Further in vivo studies are necessary to prove PN-PCX-FA potential.


Assuntos
Ácido Fólico/química , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Compostos de Boro/síntese química , Compostos de Boro/química , Varredura Diferencial de Calorimetria , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
16.
Mater Sci Eng C Mater Biol Appl ; 105: 110043, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546458

RESUMO

The gastrin-releasing peptide receptor (GRPr) is overexpressed in >75% of breast cancers. 177Lu-Bombesin (177Lu-BN) has demonstrated the ability to target GRPr and facilitate efficient delivery of therapeutic radiation doses to malignant cells. Poly(d,l­lactide­co­glycolide) acid (PLGA) nanoparticles can work as smart drug controlled-release systems activated through pH changes. Considering that paclitaxel (PTX) is a first-line drug for cancer treatment, this work aimed to synthesize and chemically characterize a novel polymeric PTX-loaded nanosystem with grafted 177Lu-BN and to evaluate its performance as a targeted controlled-release nanomedicine for concomitant radiotherapy and chemotherapy of breast cancer. PLGA(PTX) nanoparticles were synthesized using the single emulsification-solvent evaporation method with PVA as a stabilizer in the presence of PTX. Thereafter, the activation of PLGA carboxylic groups for BN attachment through the Lys1-amine group was performed. Results of the chemical characterization by FT-IR, DLS, HPLC and SEM/TEM demonstrated the successful synthesis of BN-PLGA(PTX) with a hydrodynamic diameter of 163.54 ±â€¯33.25 nm. The entrapment efficiency of paclitaxel was 92.8 ±â€¯3.6%. The nanosystem showed an adequate controlled release of the anticancer drug, which increased significantly due to the pH change from neutral (pH = 7.4) to acidic conditions (pH = 5.3). After labeling with 177Lu and purification by ultrafiltration, 177Lu-BN-PLGA(PTX) was obtained with a radiochemical purity of 99 ±â€¯1%. In vitro and in vivo studies using MDA-MB-231 breast cancer cells (GRPr-positive) demonstrated a 177Lu-BN-PLGA(PTX) specific uptake and a significantly higher cytotoxic effect for the radiolabeled nanosystem than the unlabeled BN-PLGA(PTX) nanoparticles. Using a pulmonary micrometastasis MDA-MB-231 model, the added value of 177Lu-BN-PLGA(PTX) for tumor imaging was confirmed. The 177Lu-BN-PLGA(PTX) nanomedicine is suitable as a targeted paclitaxel delivery system with concomitant radiotherapeutic effect for the treatment of GRPr-positive breast cancer.


Assuntos
Bombesina/química , Neoplasias da Mama/tratamento farmacológico , Lutécio/química , Nanomedicina , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Radioisótopos/química , Animais , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Núcleo Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Endocitose , Feminino , Humanos , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Paclitaxel/química , Paclitaxel/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de Emissão de Fóton Único
17.
Cochrane Database Syst Rev ; 9: CD004421, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31476253

RESUMO

BACKGROUND: Adjuvant chemotherapy improves survival in premenopausal and postmenopausal women with early breast cancer. Taxanes are highly active chemotherapy agents used in metastatic breast cancer. Review authors examined their role in early breast cancer. This review is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effects of taxane-containing adjuvant chemotherapy regimens for treatment of women with operable early breast cancer. SEARCH METHODS: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, CENTRAL (2018, Issue 6), the WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 16 July 2018, using key words such as 'early breast cancer' and 'taxanes'. We screened reference lists of other related literature reviews and articles, contacted trial authors, and applied no language restrictions. SELECTION CRITERIA: Randomised trials comparing taxane-containing regimens versus non-taxane-containing regimens in women with operable breast cancer were included. Studies of women receiving neoadjuvant chemotherapy were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and quality of the evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity was represented as odds ratios (ORs), and quality of life (QoL) data were extracted when present. MAIN RESULTS: This review included 29 studies (27 full-text publications and 2 abstracts or online theses). The updated analysis included 41,911 randomised women; the original review included 21,191 women. Taxane-containing regimens improved OS (HR 0.87, 95% confidence interval (CI) 0.83 to 0.92; high-certainty evidence; 27 studies; 39,180 women; 6501 deaths) and DFS (HR, 0.88, 95% CI 0.85 to 0.92; high-certainty evidence; 29 studies; 41,909 women; 10,271 reported events) compared to chemotherapy without a taxane. There was moderate to substantial heterogeneity across studies for OS and DFS (respectively).When a taxane-containing regimen was compared with the same regimen without a taxane, the beneficial effects of taxanes persisted for OS (HR 0.84, 95% CI 0.77 to 0.92; P < 0.001; 7 studies; 10,842 women) and for DFS (HR 0.84, 95% CI 0.78 to 0.90; P < 0.001; 7 studies; 10,842 women). When a taxane-containing regimen was compared with the same regimen with another drug or drugs that were substituted for the taxane, a beneficial effect was observed for OS and DFS with the taxane-containing regimen (OS: HR 0.80, 95% CI 0.74 to 0.86; P < 0.001; 13 studies; 16,196 women; DFS: HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 14 studies; 16,823 women). Preliminary subgroup analysis by lymph node status showed a survival benefit with taxane-containing regimens in studies of women with lymph node-positive disease only (HR 0.83, 95% CI 0.78 to 0.88; P < 0.001; 17 studies; 22,055 women) but less benefit in studies of women both with and without lymph node metastases or with no lymph node metastases. Taxane-containing regimens also improved DFS in women with lymph node-positive disease (HR 0.84, 95% CI 0.80 to 0.88; P < 0.001; 17 studies; 22,055 women), although the benefit was marginal in studies of women both with and without lymph node-positive disease (HR 0.95, 95% CI 0.88 to 1.02; 9 studies; 12,998 women) and was not apparent in studies of women with lymph node-negative disease (HR 0.99, 95% CI 0.86 to 1.14; 3 studies; 6856 women).Taxanes probably result in a small increase in risk of febrile neutropenia (odds ratio (OR) 1.55, 95% CI 0.96 to 2.49; moderate-certainty evidence; 24 studies; 33,763 women) and likely lead to a large increase in grade 3/4 neuropathy (OR 6.89, 95% CI 3.23 to 14.71; P < 0.001; moderate-certainty evidence; 22 studies; 31,033 women). Taxanes probably cause little or no difference in cardiotoxicity compared to regimens without a taxane (OR 0.87, 95% CI 0.56 to 1.33; moderate-certainty evidence; 23 studies; 32,894 women). Seven studies reported low-quality evidence for QoL; overall, taxanes may make little or no difference in QoL compared to chemotherapy without a taxane during the follow-up period; however, the duration of follow-up differed across studies. Only one study, which was conducted in Europe, provided cost-effectiveness data. AUTHORS' CONCLUSIONS: This review of studies supports the use of taxane-containing adjuvant chemotherapy regimens, with improvement in overall survival and disease-free survival for women with operable early breast cancer. This benefit persisted when analyses strictly compared a taxane-containing regimen versus the same regimen without a taxane or the same regimen with another drug that was substituted for the taxane. Preliminary evidence suggests that taxanes are more effective for women with lymph node-positive disease than for those with lymph node-negative disease. Considerable heterogeneity across studies probably reflects the varying efficacy of the chemotherapy backbones of the comparator regimens used in these studies. This review update reports results that are remarkably consistent with those of the original review, and it is highly unlikely that this review will be updated, as new trials are assessing treatments based on more detailed breast cancer biology.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Taxoides/uso terapêutico , Quimioterapia Adjuvante , Feminino , Humanos , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Breast Cancer Res ; 21(1): 100, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477168

RESUMO

BACKGROUND: Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. METHODS: Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. RESULTS: The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. CONCLUSION: In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. TRIAL REGISTRATION: Clinicaltrials.gov NCT02073487 , February 27, 2014.


Assuntos
/uso terapêutico , Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lapatinib/uso terapêutico , Paclitaxel/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , /administração & dosagem , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Lapatinib/administração & dosagem , Lapatinib/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Receptor ErbB-2/metabolismo , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
19.
Int J Nanomedicine ; 14: 6269-6285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496685

RESUMO

Background: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.


Assuntos
Albuminas/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Paclitaxel Ligado a Albumina/uso terapêutico , Albuminas/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Hidrodinâmica , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Nus , Paclitaxel/farmacologia , Tamanho da Partícula , Polímeros/química , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
20.
ACS Appl Mater Interfaces ; 11(40): 36371-36382, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31490057

RESUMO

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Tratamento Farmacológico , Imunoterapia , Nanopartículas/química , Neoplasias/terapia , Animais , Apresentação do Antígeno , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Imiquimode/administração & dosagem , Imiquimode/farmacocinética , Imiquimode/uso terapêutico , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Ratos Sprague-Dawley , Distribuição Tecidual
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