RESUMEN
Adjuvant oxaliplatin plus S-1 (SOX) chemotherapy for gastric cancer (GC) after D2 gastrectomy has been proven effective. There has yet to be a study that evaluates adjuvant nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1. In this single-center, retrospective study, GC patients after D2 gastrectomy received either nab-paclitaxel plus S-1 (AS group) or SOX group were recruited between January 2018 and December 2020 in The First Affiliated Hospital of Zhejiang University. Intravenous nab-paclitaxel 120 mg/m2 or 260 mg/m2 and oxaliplatin 130 mg/m2 were administered as eight 3 week cycle, especially in the AS and SOX group. Patients received S-1 twice daily with a dose of 40 mg/m2 in the two groups on days 1-14 of each cycle. The end points were disease-free survival (DFS) rate at 3 years and adverse events (AEs). There were 56 eligible patients, 28 in the AS group and 35 in the SOX group. The 3 year DFS rate was 78.0% in AS group versus 70.7% in SOX group (p = 0.46). Subgroup analysis showed that the patients with signet-ring positive in the AS group had a prolonged DFS compared with the SOX group (40.0 vs. 13.8 m, p = 0.02). The diffuse-type GC or low differentiation in the AS group was associated with numerically prolonged DFS compared with the SOX group, but the association was not statistically significant (p = 0.27 and p = 0.15 especially). Leukopenia (14.3%) were the most prevalent AEs in the AS group, while thrombocytopenia (28.5%) in the SOX group. Neutropenia (7.1% in AS group) and thrombocytopenia (22.8% in SOX group) were the most common grade 3 or 4 AEs. In this study analyzing past data, a tendency towards a greater 3 year DFS was observed when using AS regimen in signet-ring positive patients. AS group had fewer thrombocytopenia compared to SOX group. More studies should be conducted with larger sample sizes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Combinación de Medicamentos , Gastrectomía , Oxaliplatino , Ácido Oxónico , Neoplasias Gástricas , Tegafur , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Masculino , Femenino , Tegafur/administración & dosificación , Tegafur/efectos adversos , Tegafur/uso terapéutico , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Estudios Retrospectivos , Gastrectomía/métodos , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Ácido Oxónico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Quimioterapia Adyuvante/métodos , Paclitaxel Unido a Albúmina/administración & dosificación , Paclitaxel Unido a Albúmina/uso terapéutico , Adulto , Supervivencia sin Enfermedad , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/efectos adversos , Albúminas/administración & dosificaciónRESUMEN
PURPOSE: To evaluate the short-term safety of albumin-bound paclitaxel in hyperthermic intraperitoneal chemotherapy (HIPEC) during and after gastric cancer (GC) surgery. METHODS: A retrospective analysis of clinical data was conducted for GC surgery patients at Zhongnan Hospital of Wuhan University, from January 2020 to September 2022. The study group (n = 120) received HIPEC and the control group (n = 268) did not receive albumin-bound paclitaxel. Short-term safety indicators including intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery were compared between the two groups. RESULTS: There were no statistically significant differences between the two groups regarding intraoperative complications, hematological toxicity, liver and kidney function, and gastrointestinal function recovery time (P > 0.05 for all). In the study group, patients were further divided into subgroups based on dose and timing. Subgroup analysis revealed no significant differences among the different dose subgroups. However, when focusing on timing subgroups, the postoperative subgroup exhibited significantly higher white blood cell counts and bilirubin levels compared to the intraoperative subgroup, while the intraoperative subgroup had significantly higher bilirubin levels compared to both postoperative and intraoperative plus postoperative subgroups. CONCLUSION: Albumin-bound paclitaxel demonstrates good safety and tolerability in HIPEC during and after GC surgery, without increasing the risk of intraoperative complications.
Asunto(s)
Paclitaxel Unido a Albúmina , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Masculino , Quimioterapia Intraperitoneal Hipertérmica/métodos , Quimioterapia Intraperitoneal Hipertérmica/efectos adversos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Paclitaxel Unido a Albúmina/administración & dosificación , Paclitaxel Unido a Albúmina/uso terapéutico , Anciano , Adulto , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/efectos adversos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/efectos adversosRESUMEN
BACKGROUND: Combination of the prodrug technique with an albumin nano drug-loaded system is a novel promising approach for cancer treatment. However, the long-lasting and far-reaching challenge for the treatment of cancers lies in how to construct the albumin nanometer drug delivery system with lead compounds and their derivatives. METHODS: In this study, we reported the preparation of injectable albumin nanoparticles (NPs) with a high and quantitative drug loading system based on the NabTM technology of paclitaxel palmitate (PTX-PA). RESULTS: Our experimental study on drug tissue distribution in vivo demonstrated that the paclitaxel palmitate albumin nanoparticles (Nab-PTX-PA) remained in the tumor for a longer time post-injection. Compared with saline and paclitaxel albumin nanoparticles (Abraxane®), intravenous injection of Nab-PTX-PA not only reduced the toxicity of the drug in normal organs, and increased the body weight of the animals but maintained sustained release of paclitaxel (PTX) in the tumor, thereby displaying an excellent antitumor activity. Blood routine analysis showed that Nab-PTX-PA had fewer adverse effects or less toxicity to the normal organs, and it inhibited tumor cell proliferation more effectively as compared with commercial paclitaxel albumin nanoparticles. CONCLUSIONS: This carrier strategy for small molecule drugs is based on naturally evolved interactions between long-chain fatty acids (LCFAs) and Human Serum Albumin (HSA), demonstrated here for PTX. Nab-PTX-PA shows higher antitumor efficacy in vivo in breast cancer models. On the whole, this novel injectable Nab-PTX-PA has great potential as an effective drug delivery system in the treatment of breast cancer.
Asunto(s)
Paclitaxel Unido a Albúmina/farmacología , Antineoplásicos/farmacología , Paclitaxel Unido a Albúmina/administración & dosificación , Paclitaxel Unido a Albúmina/efectos adversos , Paclitaxel Unido a Albúmina/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica , Portadores de Fármacos , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Ratones , Ratones Endogámicos ICR , Nanopartículas , Tamaño de la Partícula , Distribución Aleatoria , Propiedades de SuperficieRESUMEN
BACKGROUND: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection. MATERIALS AND METHODS: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed. RESULTS: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010). CONCLUSION: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.
Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Pancreatectomía/efectos adversos , Pancreaticoduodenectomía/efectos adversos , Radioterapia Adyuvante , Radioterapia de Intensidad Modulada , Tasa de Supervivencia , Carga Tumoral , GemcitabinaRESUMEN
Abraxane, an albumin-bound paclitaxel nanoparticle formulation, is superior to conventional paclitaxel preparations because it has better efficacy against unresectable pancreatic cancer. Previous reports suggest that this better efficacy of Abraxane than conventional paclitaxel preparation is probably due to its transport through Gp60, an albumin receptor on the surface of vascular endothelial cells. The increased tumor accumulation of Abraxane is also caused by the secreted protein acid and rich in cysteine in the tumor stroma. However, the uptake mechanism of Abraxane remains poorly understood. In this study, we demonstrated that the delivery of Abraxane occurred via different receptor pathways from that of endogenous albumin. Our results showed that the uptake of endogenous albumin was inhibited by a Gp60 pathway inhibitor in the process of endocytosis through endothelial cells or tumor cells. In contrast, the uptake of Abraxane-derived HSA was less affected by the Gp60 pathway inhibitor but significantly reduced by denatured albumin receptor inhibitors. In conclusion, these data indicate that Abraxane-derived HSA was taken up into endothelial cells or tumor cells by a mechanism different from normal endogenous albumin. These new data on distinct cellular transport pathways of denatured albumin via gp family proteins different from those of innate albumin shed light on the mechanisms of tumor delivery and antitumor activity of Abraxane and provide new scientific rationale for the development of a novel albumin drug delivery strategy via a denatured albumin receptor.
Asunto(s)
Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Albúmina Sérica Humana/metabolismo , Paclitaxel Unido a Albúmina/química , Antineoplásicos/química , Línea Celular Tumoral , Dicroismo Circular , Endotelio Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Desnaturalización Proteica , Transporte de Proteínas , Sialoglicoproteínas/antagonistas & inhibidores , Sialoglicoproteínas/metabolismo , Espectrometría de Fluorescencia , Células del Estroma/metabolismoRESUMEN
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), a novel taxane formulation, was developed to avoid cremophor/ethanol-associated toxicities including peripheral neuropathy and hypersensitivity. At least 35 phase II studies using combined nab-PTX and anthracycline in neoadjuvant settings are registered in Japan. We analyzed the efficacy and safety of nab-PTX based on patient characteristics in these studies. METHODS: We conducted a meta-analysis using individual patient data (IPD) to investigate the average efficacy of nab-PTX-containing regimens as neoadjuvant chemotherapy for operable breast cancer. IPD were provided by principal investigators who agreed to participate. The primary endpoint was pathological complete response (pCR) rate of each breast cancer subtype. RESULTS: We analyzed the data of 16 studies involving 753 patients. The overall crude frequencies of pCR (ypT0 ypN0, ypT0/is ypN0, and ypT0/is ypNX) were 18.1, 26.0, and 28.6%, respectively. Specifically, the frequencies were 6.7, 10.2, and 13.4% for luminal (n = 343); 40.5, 63.5, and 68.9% for human epidermal growth factor receptor 2 (HER2)-rich, (n = 74); 21.9, 40.6, and 42.7% for luminal/HER2 (n = 96); and 26.3, 31.5, and 32.3% for triple-negative breast cancers (TNBC) (n = 232). The multivariate analyses indicated that HER2 positivity, TNBC, high Ki-67, high nuclear grade, and weekly nab-PTX administration were significantly associated with the pCR. The proportion of hematological toxicities (neutropenia (39.7%) and leukopenia (22.5%)), peripheral sensory neuropathy (9.7%), myalgia (5.7%), and arthralgia (4.7%) was higher than grade 3 adverse events, but most patients recovered. CONCLUSIONS: Nab-PTX is a safe and acceptable chemotherapeutic agent in neoadjuvant settings, particularly for aggressive cancers. UMIN-CTR#: UMIN000028774.
Asunto(s)
Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel Unido a Albúmina/efectos adversos , Antraciclinas/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Receptor ErbB-2 , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has exhibited clinical efficacy in breast cancer treatment, but toxicities can be yielded more at the same time. We did this meta-analysis aiming to unambiguously compare nab-PTX with conventional solvent-based paclitaxel in breast cancer patients of all stages. METHOD: Pubmed, EMBASE, Cochrane Library, Chinese Biomedical database, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodical database, and WangFang database were searched for head-to-head randomized controlled trials of nab-PTX and solvent-based paclitaxel in breast cancer. Other sources will also be searched like Google Scholar and gray literatures. Two researchers will independently search the database and extract data from the articles. Risk of bias will be assessed using the Cochrane Collaboration's tool. Objective tumor response rate, chemotherapy completion rate after 4 or 6 cycles, and toxicity will be primary outcomes. Disease control rate, overall survival, and progression-free survival/disease-free survival will be included in secondary outcomes. Risk ratio with 95% confidence interval was used for dichotomous variables while hazard ratio was used for time-to-event outcomes. The following 3 data sets will all be considered when synthesizing the data: intention-to-treat population, those who actually received taxanes treatment, and those who were actually assessed. All the analyses were done using Review Manager Software 5.3. Any disagreements in study selection, data collection, and analysis will be resolved by a third investigator. RESULTS AND CONCLUSION: This study is aim to evaluate the efficacy and safety of nab-PTX compared with PTX in breast cancer treatment as well as to find the best dose or schedule and identify the benefit population. This meta-analysis could provide evidence for clinicians to make a better choice between nab-PTX and PTX in different specific contexts. PROSPERO REGISTRATION NUMBER: CRD42019117912.
Asunto(s)
Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel Unido a Albúmina/efectos adversos , Antineoplásicos/efectos adversos , Toma de Decisiones Clínicas , Femenino , Humanos , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
Combination chemotherapy with two or more complimentary drugs has been widely used for clinical cancer treatment. However, the efficacy and side effects of combination chemotherapy still remain a challenge. Here, we constructed an albumin-stabilized layered double hydroxide nanoparticle (BLDH) system to simultaneously load and deliver two widely used anti-tumor drugs, i.e. 5-fluorouracil (5FU) and albumin-bound PTX (Abraxane, ABX) for colorectal cancer treatment. The cellular uptake test has revealed that 5FU-ABX encapsulated BLDH (BLDH/5FU-ABX) nanoparticles were efficiently internalized by the colorectal cancer cell (HCT-116), synergistically inducing apoptosis of colon cancer cells. The in vivo test has demonstrated that BLDH/5FU-ABX nanomedicine significantly inhibited the tumor growth after three intravenous injections, without any detectable side effects. The enhanced therapeutic effectiveness is attributed to efficient accumulation of BLDH/5FU-ABX at tumor sites and acid-sensitive release of co-loaded drugs. Thus, combination chemotherapy based on BLDH/5FU-ABX nanomedicine would be a new strategy for colorectal cancer treatment.
Asunto(s)
Albúminas/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Hidróxidos/química , Nanomedicina , Nanopartículas/química , Paclitaxel Unido a Albúmina/administración & dosificación , Paclitaxel Unido a Albúmina/uso terapéutico , Animales , Sinergismo Farmacológico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Células HCT116 , Humanos , Inyecciones Intravenosas , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC. METHODS: This study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital. RESULTS: A total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4-4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1-4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83-1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3-12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5-12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61-1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group. CONCLUSIONS: The combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Paclitaxel Unido a Albúmina/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/química , Paclitaxel/administración & dosificación , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Tasa de Supervivencia , RamucirumabRESUMEN
Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with breast cancer stem-like cells (CSCs). Although Taxol (micelle formulation of paclitaxel) is the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle of paclitaxel, showed lower plasma concentration compared to Taxol in both human and animal models, but it is not clear why Abraxane showed superior efficacy to Taxol in treatment of metastatic breast cancer in humans. In this study, we intend to investigate if Abraxane eliminates CSCs for its better efficacy. The results showed that Abraxane showed similar cytotoxicity in SUM149 cells in comparison with Taxol. Although Abraxane showed 3- to 5-fold lower blood drug concentration compared to Taxol, it achieved similar tumor drug concentration and 10-fold higher tumor/plasma ratio in SUM149 xenograft NOD/SCID mouse model. In addition, Abraxane and Taxol showed similar efficacy to shrink the tumor size in orthotopic breast cancer NOD/SCID mouse model. However, Abraxane decreased breast CSCs frequency by 3- to 9-fold, while Taxol increased breast CSCs frequency in an orthotopic breast cancer NOD/SCID mouse model. Furthermore, Abraxane increased 3- to 15-fold intracellular uptake in both ALDH+ CSCs and differentiated ALDH- cells in comparison with Taxol, which provides a mechanism for Abraxane's superior efficacy to eliminate CSCs in comparison with Taxol. Our data suggest albumin nanoparticle Abraxane may have a broad implication to enhance drug's efficacy by eliminating breast cancer stem cells for treatment of metastatic diseases.
Asunto(s)
Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Paclitaxel Unido a Albúmina/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer-associated fibroblasts (CAFs) are crucial for forming the desmoplastic stroma that is associated with chemoresistance in pancreatic ductal adenocarcinoma (PDAC). In the clinic, depleting dense stroma in PDAC tumor tissue is a promising chemotherapeutic strategy. In this study, we report that the local hyperthermia can reduce the number of CAFs in the PDAC PDX mouse mode, which further augments chemotherapeutic efficiency in the PDAC therapy. To achieve this goal, a photothermal-chemotherapeutic agent termed as Abraxane@MoSe2 as a vehicle-saving theranostic probe is prepared by simply mixing an FDA-approved Abraxane and hydrophobic MoSe2 nanosheets via electrostatic and hydrophobic interactions. After labeling with indocyanine green (ICG) dye on the Abraxane@MoSe2, a relatively high fluorescence signal (near infrared second (NIR II)) in PDX tumors can be obtained, which can be precisely imaging-guide local photothermal-chemotherapy upon the 808 nm laser irradiation in vivo. Importantly, the synergy therapeutic efficiency in PDAC is enhanced by the photothermal effect reduction of the number of CAFs, which is confirmed viaα-SMA and vimentin immunofluorescence analysis. This combined therapeutic strategy may provide a new sight for PDAC therapy.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos/administración & dosificación , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Molibdeno/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Selenio/administración & dosificación , Paclitaxel Unido a Albúmina/química , Paclitaxel Unido a Albúmina/efectos de la radiación , Animales , Antineoplásicos/química , Antineoplásicos/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Rayos Láser , Ratones Desnudos , Molibdeno/química , Molibdeno/efectos de la radiación , Fotoquimioterapia , Selenio/química , Selenio/efectos de la radiaciónRESUMEN
BACKGROUND: Carboplatin plus nanoparticle albumin-bound paclitaxel (nab-PTX) is one of the available first-line treatments for non-small cell lung cancer (NSCLC) patients. However, the efficacy of carboplatin plus nab-PTX as second-line, remains unknown. We examined the efficacy of carboplatin plus nab-PTX after cisplatin plus pemetrexed in non-squamous NSCLC patients. METHODS: We retrospectively reviewed advanced non-squamous NSCLC patients who received carboplatin plus nab-PTX as a second-line chemotherapy regimen after cisplatin plus pemetrexed in our hospital between March 2013 and December 2017. We assessed clinical characteristics, efficacy, and toxicities. RESULTS: Forty-four patients were recruited. The overall response rate (ORR) was 29% and the disease control rate (DCR), 69%. The median progression-free survival (mPFS) was 3.7 months (95% CI: 2.4-5.5 months) and the median overall survival, 16.6 months (95% CI:8.8-19.5 months). We assessed the ORR and mPFS using the best overall response in the prior regimen. The ORR and mPFS were better in the PD group (ORR; 44% and mPFS: 5.6 months). CONCLUSIONS: Carboplatin plus nab-PTX after cisplatin plus pemetrexed in non-squamous NSCLC patients is a treatment option. There were several cases where cisplatin plus pemetrexed was not effective, but Carboplatin plus nab-PTX was.
Asunto(s)
Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Nanopartículas , Paclitaxel/administración & dosificación , Pemetrexed/administración & dosificación , Adulto , Anciano , Paclitaxel Unido a Albúmina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Cisplatino/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Pemetrexed/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Tumor-associated macrophages (TAMs) have been shown to both aid and hinder tumor growth, with patient outcomes potentially hinging on the proportion of M1, pro-inflammatory/growth-inhibiting, to M2, growth-supporting, phenotypes. Strategies to stimulate tumor regression by promoting polarization to M1 are a novel approach that harnesses the immune system to enhance therapeutic outcomes, including chemotherapy. We recently found that nanotherapy with mesoporous particles loaded with albumin-bound paclitaxel (MSV-nab-PTX) promotes macrophage polarization towards M1 in breast cancer liver metastases (BCLM). However, it remains unclear to what extent tumor regression can be maximized based on modulation of the macrophage phenotype, especially for poorly perfused tumors such as BCLM. Here, for the first time, a CRISPR system is employed to permanently modulate macrophage polarization in a controlled in vitro setting. This enables the design of 3D co-culture experiments mimicking the BCLM hypovascularized environment with various ratios of polarized macrophages. We implement a mathematical framework to evaluate nanoparticle-mediated chemotherapy in conjunction with TAM polarization. The response is predicted to be not linearly dependent on the M1:M2 ratio. To investigate this phenomenon, the response is simulated via the model for a variety of M1:M2 ratios. The modeling indicates that polarization to an all-M1 population may be less effective than a combination of both M1 and M2. Experimental results with the CRISPR system confirm this model-driven hypothesis. Altogether, this study indicates that response to nanoparticle-mediated chemotherapy targeting poorly perfused tumors may benefit from a fine-tuned M1:M2 ratio that maintains both phenotypes in the tumor microenvironment during treatment.
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Paclitaxel Unido a Albúmina/administración & dosificación , Neoplasias de la Mama/terapia , Neoplasias Hepáticas/terapia , Activación de Macrófagos/genética , Macrófagos/inmunología , Modelos Biológicos , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Sistemas CRISPR-Cas/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Ingeniería Celular , Línea Celular Tumoral/trasplante , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Femenino , Humanos , Liposomas , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Ratones , Nanopartículas , Esferoides Celulares , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic antitumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLC) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the antitumor activity in patients with advanced SQCLCs. PATIENTS AND METHODS: This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1,000 mg/m2) plus ABP (100 mg/m2) in a 3-week on, 1-week off schedule during stage I and a 2-week on, 1-week off schedule in stage II. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy. RESULTS: Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient [ORR 59%; 95% confidence interval (CI), 42%-74%]. Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI, 6.7-10.5) months. There were no unexpected toxicities. CONCLUSIONS: Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable with carboplatin plus taxane plus pembrolizumab.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de Células Escamosas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Paclitaxel Unido a Albúmina/administración & dosificación , Biomarcadores de Tumor/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/patología , Seguridad del Paciente , Tasa de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND/AIM: The objective of this phase I study was to determine the maximum-tolerated dose (MTD) and recommended dose (RD) of combination therapy with weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and cyclophosphamide (CPA) in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Five patients who had human epidermal growth factor receptor 2 (HER2) negative MBC were recruited in this study. They received nab-paclitaxel at dose levels of 100-150 mg once a week for three weeks, repeated every 4 weeks, and CPA (600 mg/m2) administered on day 1. RESULTS: No patient had grade 4 toxicity, however, two patients discontinued protocol treatment due to adverse events at level 2. Thus, the Data and Safety Monitoring Committee recommended the MTD of nab-paclitaxel and CPA to be determined at level 2. CONCLUSION: The combination therapy with weekly nab-paclitaxel and CPA was tolerable, and the RD for these drugs for MBC were 100 and 600 mg/m2, respectively.
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Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Adulto , Anciano , Paclitaxel Unido a Albúmina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Resultado del Tratamiento , Adulto JovenRESUMEN
Background and objective: Paclitaxel protein-bound particles for injectable suspension (nab-paclitaxel) showed many advantages in safety, effectiveness, and convenience. Different from conventional formulations, the bioequivalence evaluation of nab-paclitaxel formulations requires to determine the total amount of paclitaxel in plasma and the unbound paclitaxel to reflect their in vivo disposition. This study aimed to develop an analytical method to quantify the total and unbound paclitaxel in plasma and evaluate the bioequivalence of two formulations of nab-paclitaxel in patients with breast cancer. Materials and methods: An open-label, randomized, two-period crossover study was completed among 24 Chinese patients with breast cancer. The patients were randomized to receive either the test formulation on cycle 1 day 1 and after 21 days in cycle 2 day 1 by the reference formulation (Abraxane®), or vice versa. Rapid equilibrium dialysis was adopted to separate the unbound paclitaxel in human plasma. Total and unbound paclitaxel concentrations were measured by the validated liquid chromatography-tandem mass spectrometry methods over the range of 5.00-15,000 and 0.200-200 ng/mL, respectively. The bioequivalence of the test formulation to the reference formulation was assessed using the Food and Drug Administration and European Medicines Agency guidelines. Results: All the 90% confidence intervals (CIs) of the geometric mean ratios fell within the predetermined acceptance range. The 90% CIs for the area under the concentration-time curve (AUC) from 0 h to 72 h (AUC0-t), AUC from time zero to infinity (AUC0-∞), and peak plasma concentrations (Cmax) for total paclitaxel were 92.03%-98.05%, 91.98%-99.37%, and 91.37%-99.36%, respectively. The 90% CIs of AUC0-t, AUC0-∞, and Cmax for unbound paclitaxel were 86.77%-97.88%, 86.81%-97.88%, and 87.70%-98.86%, respectively. Conclusion: Bioequivalence between the two nab-paclitaxel formulations was confirmed for total and unbound paclitaxel at the studied dose regimen.
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Paclitaxel Unido a Albúmina/farmacocinética , Antineoplásicos Fitogénicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Administración Oral , Paclitaxel Unido a Albúmina/administración & dosificación , Paclitaxel Unido a Albúmina/sangre , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Pueblo Asiatico , Neoplasias de la Mama/sangre , Cromatografía Liquida , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Tamaño de la Partícula , Espectrometría de Masas en Tándem , Equivalencia TerapéuticaRESUMEN
The poor solubility of paclitaxel (PTX), the most commonly used anticancer drug (Taxol®), has long hindered the development of successful formulations. In 2005, the launch of Abraxane®, a human albumin-based preparation of PTX, competed with Taxol® in the commercial market. The success of Abraxane pushed other generic preparations aside, sparking competition among the global pharmaceutical companies to develop the novel and superior PTX nanotechnology-driven formulations. Unsurprisingly, the success underlying with cancer treatment using nano PTX therapy has now entered into a new era of drug development, patentability, preclinical and clinical evaluation, leading eventually to a significant increase in the regulatory approval of the products. The present article aims to provide recent progress in the development of nano PTX formulations by various pharmaceutical companies for safe and effective drug therapies for patients benefit.
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Paclitaxel Unido a Albúmina/farmacología , Antineoplásicos Fitogénicos/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel Unido a Albúmina/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Humanos , Polímeros/química , SolubilidadRESUMEN
PURPOSE: Neoadjuvant trastuzumab combined with anthracycline and taxane is now considered a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A less toxic, non-anthracycline regimen has been considered as a treatment option for patients with node-negative small tumors. Estrogen receptor-negative and HER2-positive (pure HER2) tumors are more likely to achieve a pathological complete response (pCR). This study evaluates the activity and safety of neoadjuvant nanoparticle albumin-bound paclitaxel (nab-PTX) plus trastuzumab for pure HER2 breast cancer in patients with low risk of relapse. METHODS: We treated patients with tumors measuring ≤ 3 cm, node-negative, pure HER2 breast cancer using neoadjuvant nab-PTX 260 mg/m2 with trastuzumab every 3 weeks for four cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery conversion rate, safety, and disease-free survival. Depending on the pathological findings of surgical specimens, the administration of adjuvant anthracycline could be omitted. RESULTS: Eighteen patients were enrolled. No patient required dose delays or reductions; none showed disease progression, and all patients underwent surgery as scheduled. Of the 18 patients, 66.7% achieved pCR, and the adjuvant anthracycline regimen was omitted for all patients. The incidence of severe adverse events was quite low. CONCLUSION: This less toxic, anthracycline-free regimen appears to be a significantly effective neoadjuvant therapy for patients with pure HER2 breast cancer at low relapse risk.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/terapia , Receptor ErbB-2/metabolismo , Adulto , Anciano , Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Prospectivos , Trastuzumab/administración & dosificación , Resultado del TratamientoAsunto(s)
Neoplasias Pancreáticas/mortalidad , Anciano , Anciano de 80 o más Años , Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Comorbilidad , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Diabetes Mellitus/epidemiología , Dieta , Resistencia a Antineoplásicos , Detección Precoz del Cáncer , Fluorouracilo/administración & dosificación , Predisposición Genética a la Enfermedad , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Metástasis de la Neoplasia , Oxaliplatino/administración & dosificación , Cuidados Paliativos , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/terapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Pronóstico , Radiocirugia , Factores de Riesgo , España/epidemiología , GemcitabinaRESUMEN
Polygeline is a highly promising drug carrier-oriented material for important applications in pharmacy field due to its low-cost and unique properties similar to albumin. In this study, polygeline-bound paclitaxel nanoparticles (Npb-PTXS) were fabricated through a combination of low-pressure emulsification and high-pressure homogenization. The effects of a series of production parameters on mean particle size, particle size distribution and drug loading of Npb-PTXS were systematically evaluated. The characteristics of Npb-PTXS, such as surface morphology, physical status of paclitaxel (PTX) in Npb-PTXS, redispersibility of Npb-PTXS in purified water and bioavailability in vivo were also investigated. It is revealed that the optimal preparation conditions included an aqueous phase pH value of about 6.5, protein mass concentration of 0.33%, with mass ratio of PTX to protein of 30%, high pressure of 1200 bar, high-pressure passes of 25 times and low-pressure emulsifying passes of 20 times. Obtained Npb-PTXS shows good resolubility compared to commercially available Abraxane®, containing round or oval shaped particles with mean particle size of around 188.3 nm, polydispersity index of 0.163 and zeta potential of -31.1 mV. PTX in Npb-PTX is amorphous, and its content is approximately 12.04%. Encapsulation efficiency of Npb-PTXS reaches 81.2%. Moreover, in vivo pharmacokinetic studies showed that the intravenous relative bioavailability of Npb-PTXS to Abraxane was 83.89%.