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1.
Anticancer Res ; 40(9): 5181-5189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878806

RESUMO

BACKGROUND/AIM: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. MATERIALS AND METHODS: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. RESULTS: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. CONCLUSION: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.


Assuntos
Antineoplásicos/farmacologia , Modelos Teóricos , Dinâmica não Linear , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
2.
Nat Commun ; 11(1): 4615, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934241

RESUMO

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.


Assuntos
Aminoquinolinas/química , Antineoplásicos/química , Sistemas de Liberação de Medicamentos/métodos , Lisossomos/efeitos dos fármacos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Aminoquinolinas/administração & dosagem , Aminoquinolinas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/instrumentação , Humanos , Nanomedicina/instrumentação , Nanopartículas/química , Neoplasias/fisiopatologia , Ratos , Ratos Sprague-Dawley
3.
Int J Nanomedicine ; 15: 6385-6399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922007

RESUMO

Purpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.


Assuntos
Portadores de Fármacos/química , Esomeprazol/farmacologia , Sistema Fagocitário Mononuclear/citologia , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Endocitose , Esomeprazol/farmacocinética , Esomeprazol/uso terapêutico , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Células RAW 264.7 , Distribuição Tecidual/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo
4.
N Engl J Med ; 383(13): 1207-1217, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32955176

RESUMO

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética
5.
Int J Nanomedicine ; 15: 3851-3868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764919

RESUMO

Purpose: The aim of this study was to develop a means of improving the bioavailability and anticancer activity of urushiol by developing an urushiol-loaded novel tumor-targeted micelle delivery system based on amphiphilic block copolymer poly(ethylene glycol)-b-poly-(ß-amino ester) (mPEG-PBAE). Materials and Methods: We synthesized four different mPEG-PBAE copolymers using mPEG-NH2 with different molecular weights or hydrophobicity levels. Of these, we selected the mPEG5000-PBAE-C12 polymer and used it to develop an optimized means of preparing urushiol-loaded micelles. Response surface methodology was used to optimize this formulation process. The micellar properties, including particle size, pH sensitivity, drug release dynamics, and critical micelle concentrations, were characterized. We further used the MCF-7 human breast cancer cell line to explore the cytotoxicity of these micelles in vitro and assessed their pharmacokinetics, tissue distribution, and antitumor activity in vivo. Results: The resulting micelles had a mean particle size of 160.1 nm, a DL value of 23.45%, and an EE value of 80.68%. These micelles were found to release their contents in a pH-sensitive manner in vitro, with drug release being significantly accelerated at pH 5.0 (98.74% in 72 h) without any associated burst release. We found that urushiol-loaded micelles were significantly better at inducing MCF-7 cell cytotoxicity compared with free urushiol, with an IC50 of 1.21 mg/L. When these micelles were administered to tumor model animals in vivo, pharmacokinetic analysis revealed that the total AUC and MRT of these micelles were 2.28- and 2.53-fold higher than that of free urushiol, respectively. Tissue distribution analyses further revealed these micelles to mediate significantly enhanced tumor urushiol accumulation. Conclusion: The pH-responsive urushiol-loaded micelles described in this study may be ideally suited for clinical use for the treatment of breast cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Catecóis/química , Catecóis/farmacologia , Micelas , Polietilenoglicóis/química , Polímeros/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Catecóis/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula , Distribuição Tecidual
6.
Yakugaku Zasshi ; 140(8): 1001-1006, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741857

RESUMO

Ascertaining the absorption, distribution, metabolism, and excretion (ADME) profile of drugs is one of the most crucial factors in the process of drug discovery. Since it is important to combine water solubility and cell permeability within the compound to achieve the desired ADME properties, an appropriate balance between lipophilicity and hydrophilicity is required. It is often necessary to facilitate hydrophilicity of very hydrophobic candidates, because quite lipophobic molecules are rarely hit as positive in molecular-targeted or cell-based screenings. For that purpose, it has been popular to conjugate hydrophobic molecules with polyethylene glycol (PEG). However, PEG is a polymer, and PEG-conjugated molecules are not uniform. Besides, the dosage should be much increased compared with the original molecule due to the increase in molecular weight. Therefore we have been developing alternative ways to endow hydrophobic compounds with extra hydrophilicity by conjugating with symmetrically branched glycerol oligomers. This technology is versatile and easily applicable to various hydrophobic compounds. Water-solubility of fenofibrate, one of the most hydrophobic medicines in clinical use, was facilitated by a factor of more than 2000, and its lipid-lowering effect in vivo improved more than ten-fold, by simply conjugating with branched glycerol trimer, for instance. Here we will briefly introduce the basic concepts and our successful experiences of applying branched glycerol oligomers including antitumor agents in terms of water-solubility, pharmacological effects, and pharmacokinetics, and merits and current issues will be discussed in this review.


Assuntos
Antineoplásicos , Glicerol/química , Interações Hidrofóbicas e Hidrofílicas , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ácidos Fíbricos , Polietilenoglicóis/química , Polímeros , Solubilidade , Água
7.
Science ; 369(6506)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820094

RESUMO

Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-ß secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Membrana/metabolismo , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Humanos
8.
Crit Rev Ther Drug Carrier Syst ; 37(3): 205-227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749138

RESUMO

In this review, we describe the advances in oral drug delivery approaches for taxanes for successful therapeutic outcome. Taxanes (paclitaxel and docetaxel) have unwanted pharmacokinetic profiles when they are given in their current dosage forms. Taxanes have low bioavailability, are extensively metabolized by CYP3A, and have a high affinity for P-glycoprotein. Regardless of dosage schedule, the overall docetaxel or paclitaxel dose that a patient can tolerate at a given interval remains similar. Currently, there are no commercially available oral taxane nanoformulations, and there are still several challenges to overcome. Nano-based formulations may offer the best solutions to problems involving the safety and effectiveness of taxane delivery. Thus, further research is necessary before such taxane nanoformulations can be manufactured for clinical use.


Assuntos
Docetaxel/administração & dosagem , Paclitaxel/administração & dosagem , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Ensaios Clínicos como Assunto , Docetaxel/química , Docetaxel/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacocinética
9.
Int J Nanomedicine ; 15: 5333-5344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801692

RESUMO

Purpose: Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment. Methods: CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo. Results: The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile. Conclusion: In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.


Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Soroalbumina Bovina/administração & dosagem , Taxoides/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cromatografia Líquida , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/química , Neoplasias da Próstata/diagnóstico por imagem , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacocinética , Espectrometria de Massas em Tandem , Taxoides/farmacocinética , Distribuição Tecidual
10.
Int J Nanomedicine ; 15: 5459-5471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801700

RESUMO

Purpose: Indocyanine green (ICG), a near infrared (NIR) dye clinically approved in medical diagnostics, possesses great heat conversion efficiency, which renders itself as an effective photosensitizer for photothermal therapy (PTT) of cancer. However, there remain bottleneck challenges for use in PTT, which are the poor photo and plasma stability of ICG. To address these problems, in this research, ICG-loaded silver nanoparticles were prepared and evaluated for the applicability as an effective agent for photothermal cancer therapy. Methods and Results: PEGylated bovine serum albumin (BSA)-coated silver core/shell nanoparticles were synthesized with a high loading of ICG ("PEG-BSA-AgNP/ICG"). Physical characterization was carried out using size analyzer, transmission electron microscopy, and Fourier transform infrared spectrophotometry to identify successful preparation and size stability. ICG-loading content and the photothermal conversion efficiency of the particles were confirmed with inductively coupled plasma mass spectrometry and laser instruments. In vitro studies showed that the PEG-BSA-AgNP/ICG could provide great photostability for ICG, and their applicability for PTT was verified from the cellular study results. Furthermore, when the PEG-BSA-AgNP/ICG were tested in vivo, study results exhibited that ICG could stably remain in the blood circulation for a markedly long period (plasma half-life: 112 min), and about 1.7% ID/g tissue could be accumulated in the tumor tissue at 4 h post-injection. Such nanoparticle accumulation in the tumor enabled tumor surface temperature to be risen to 50°C (required for photo-ablation) by laser irradiation and led to successful inhibition of tumor growth in the B16F10 s.c. syngeneic nude mice model, with minimal systemic toxicity. Conclusion: Our findings demonstrated that PEG-BSA-AgNPs could serve as effective carriers for delivering ICG to the tumor tissue with great stability and safety.


Assuntos
Antineoplásicos/farmacologia , Nanopartículas Metálicas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Estabilidade de Medicamentos , Difusão Dinâmica da Luz , Meia-Vida , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacocinética , Melanoma Experimental/tratamento farmacológico , Camundongos Endogâmicos ICR , Camundongos Nus , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química , Soroalbumina Bovina/química , Prata/química , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Cancer Treat Rev ; 89: 102062, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32659623

RESUMO

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.


Assuntos
Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/administração & dosagem , Anilidas/efeitos adversos , Anilidas/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/metabolismo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Neoplasias Renais/metabolismo , Modelos Estatísticos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Proteína Tirosina Quinases/administração & dosagem , Receptores Proteína Tirosina Quinases/efeitos adversos , Receptores Proteína Tirosina Quinases/farmacocinética
12.
Proc Natl Acad Sci U S A ; 117(30): 17535-17542, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661159

RESUMO

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl2 (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ródio , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Pareamento Incorreto de Bases/efeitos dos fármacos , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Células HCT116 , Humanos , Camundongos , Estrutura Molecular , Ródio/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
13.
AAPS PharmSciTech ; 21(5): 174, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32548786

RESUMO

Hepatocellular carcinoma (HCC) is a foremost type of cancer problem in which asialoglycoprotein receptors are overexpressed. In this study, asialoglycoprotein receptor-targeted nanoformulation (galactose-conjugated TPGS micelles) loaded with docetaxel (DTX) was developed to achieve its site-specific delivery for HCC therapy. The pharmaceutical characteristics like shape morphology, average particle size and zeta potential, drug entrapment efficiency, and in vitro release kinetics of developed system were evaluated. DTX-loaded galactosylated TPGS (DTX-TPGS-Gal) micelles and TPGS micelles (DTX-TPGS) were having 58.76 ± 1.82% and 54.76 ± 1.42% entrapment of the DTX, respectively. In vitro drug release behavior from micelles was controlled release. Cytotoxicitiy (IC50) of DTX-TPGS-Gal formulation on HepG2 cell lines was significantly (p ≤ 0.01) lower (6.3 ± 0.86 µg/ml) than DTX-TPGS (9.06 ± 0.82 µg/ml) and plain DTX (16.06 ± 0.98 µg/ml) indicating higher efficacy of targeted formulation. Further, in vivo biodistribution studies in animal model showed maximum drug accumulation at target site, i.e., the liver in the case of DTX-TPGS-Gal as compared with non-targeted one. It is concluded from the findings that TPGS-Gal micelles can be utilized for targeted drug delivery of cytotoxic drugs towards HCC with minimized side effects. Graphical abstract.


Assuntos
Carcinoma Hepatocelular/metabolismo , Docetaxel/química , Sistemas de Liberação de Medicamentos/métodos , Galactose/química , Neoplasias Hepáticas/metabolismo , Vitamina E/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Desenvolvimento de Medicamentos/métodos , Feminino , Galactose/administração & dosagem , Galactose/farmacocinética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Distribuição Aleatória , Ratos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Vitamina E/administração & dosagem , Vitamina E/farmacocinética
14.
Eur J Med Chem ; 200: 112356, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32485531

RESUMO

Resveratrol is a natural polyphenolic stilbene isolated from various plants, foods and beverages with a broad spectrum of biological and pharmacological properties through modulating diverse targets and signaling pathways. Particularly, it has attracted a great deal of attention as a promising and multitarget anticancer agent due to its potential use in chemoprevention and chemotherapy of various tumors. However, unfavorable pharmacokinetics/pharmacodynamics profile such as poor bioavailability restricted its applications. Therefore, medicinal chemists have synthesized a lot of novel derivatives and analogues of resveratrol using different modification strategies to overcome these limitations and improve anticancer efficacy. Herein, we reviewed the design, synthesis, structure-activity relationship and mechanism of the most potent and privileged resveratrol-based compounds that showed promising anticancer activities in the last five years. We classified these compounds into the ten different categories based on their chemical structure similarities.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Resveratrol/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Disponibilidade Biológica , Humanos , Resveratrol/análogos & derivados , Resveratrol/síntese química , Resveratrol/farmacocinética , Relação Estrutura-Atividade
15.
Int J Nanomedicine ; 15: 2987-2998, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431497

RESUMO

Background: Emerging cancer therapy requires highly sensitive diagnosis in combination with cancer-targeting therapy. In this study, a self-assembled pH-sensitive curcumin (Cur)-loaded nanoparticle of 99mTc radiolabeled hyaluronan-cholesteryl hemisuccinate conjugates (HA-CHEMS) and D-a-tocopheryl polyethylene glycol succinate (TPGS) was prepared for breast cancer synergistic theranostics. Materials and Methods: The synthesized amphiphilic HA-CHEMS conjugates and TPGS self-assembled into Cur-loaded nanoparticles (HA-CHEMS-Cur-TPGS NPs) in an aqueous environment. The physicochemical properties of HA-CHEMS-Cur-TPGS NPs were characterized by transmission electron microscopy (TEM) and dynamic lighter scattering (DLS). The in vitro cytotoxicity of HA-CHEMS-Cur-TPGS NPs against breast cancer cells was evaluated by using the methyl thiazolyl tetrazolium (MTT) assay. Moreover, the in vivo animal experiments of HA-CHEMS-Cur-TPGS NPs including SPECT/CT imaging biodistribution and antitumor efficiency were investigated in 4T1 tumor-bearing BALB/c mice; furthermore, pharmacokinetics were investigated in healthy mice. Results: HA-CHEMS-Cur-TPGS NPs exhibited high curcumin loading, uniform particle size distribution, and excellent stability in vitro. In the cytotoxicity assay, HA-CHEMS-Cur-TPGS NPs showed remarkably higher cytotoxicity to 4T1 cells with an IC50 value at 38 µg/mL, compared with free curcumin (77 µg/mL). Moreover, HA-CHEMS-Cur-TPGS NPs could be effectively and stably radiolabeled with 99mTc. The SPECT images showed that 99mTc-HA-CHEMS-Cur-TPGS NPs could target the 4T1 tumor up to 4.85±0.24%ID/g at 4 h post-injection in BALB/c mice. More importantly, the in vivo antitumor efficacy studies showed that HA-CHEMS-Cur-TPGS NPs greatly inhibited the tumor growth without resulting in obvious toxicities to major organs. Conclusion: The results indicated that HA-CHEMS-Cur-TPGS NPs with stable 99mTc labeling and high curcumin-loading capacity hold great potential for breast cancer synergistic theranostics.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Curcumina/uso terapêutico , Ácido Hialurônico/química , Nanopartículas/química , Tecnécio/química , Nanomedicina Teranóstica , alfa-Tocoferol/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Curcumina/farmacocinética , Curcumina/farmacologia , Feminino , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Distribuição Tecidual/efeitos dos fármacos
16.
Int J Nanomedicine ; 15: 2751-2764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368053

RESUMO

Introduction: A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer. Methods: The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect. Results: The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo. Discussion: Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.


Assuntos
Antineoplásicos/administração & dosagem , Dendrímeros/química , Portadores de Fármacos/administração & dosagem , Nylons/química , Transferrina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Dendrímeros/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Células Hep G2 , Histidina/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Oxirredução , Polietilenoglicóis/química , Succinimidas/química , Transferrina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Yakugaku Zasshi ; 140(5): 641-648, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378664

RESUMO

Traditionally, anticancer drug discovery research has been conducted based on immortalized cancer cell lines, either cultured in vitro or grown in vivo. In the USA and Europe, patient derived xenograft (PDX) model is rapidly expelling traditional in vitro and in vivo models due to the good predictability of clinical outcome and its nature of retaining characteristics and heterogeneity in the original tumor. Furthermore, a significant association was also reported between drug responses in patient and corresponding PDX as high as 87%. We are preparing a PDX model for Japanese cancer patients including drug resistance examples and rare cancers. Using the established PDX model, we confirmed the possibility that the tumor microenvironment might affect the efficacy and distribution of drugs even if the target receptor is expressed in tumor sites as compared to the cell line (CDX) model, which has been widely used in drug discovery. Interestingly, although expressing a target receptor in viable tumor cells, we also have found a PDX model with a lower distribution of molecular target drug. Therefore we will evaluate the usefulness of the PDX model in drug development by exploring new biomarkers and elucidating the mechanisms of drug resistance in target tumors. Moreover, pharmaco-imaging system will allow us to visualize the exposure and distribution of drugs in tumors at macro and micro levels. Finally, we evaluate relations between distribution of drugs in the tumor microenvironment including target tumor cells, neovessels, stromal cells, immune cells, and fibroblasts.


Assuntos
Antineoplásicos/farmacocinética , Desenvolvimento de Medicamentos , Terapia de Alvo Molecular , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Animais , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Distribuição Tecidual , Microambiente Tumoral
18.
Xenobiotica ; 50(11): 1323-1331, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32369406

RESUMO

The compound 20(S),25-epoxydammarane-3ß,12ß,24α-triol (24-hydroxy-panaxadiol or 24-OH-PD), isolated from the red Panax ginseng CA Meyer possesses anticancer activity. Our aim was to study the pharmacokinetic characteristics of 24-OH-PD, which is essential for pre-clinical research during the development of new drugs. In this study, a simple and sensitive ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was established and used for studying the pharmacokinetics, in vitro protein binding, tissue distribution, and elimination profiles of 24-OH-PD in rats. 24-OH-PD was characterized by linear pharmacokinetics in the dose range of 2.5-10 mg/kg and had relatively longer half-life (4.82-5.45 h) than the other ginsenosides. It had a wide tissue distribution profile in rats and was primarily distributed in the lung. Within 96 h of intravenous administration, 13.84% of 24-OH-PD was excreted out via feces and 0.02% via urine in its unchanged form. In conclusion, a simple LC-MS/MS method with high sensitivity and selectivity was established for the quantification of 24-OH-PD.


Assuntos
Antineoplásicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Animais , Antineoplásicos/metabolismo , Líquidos Corporais , Medicamentos de Ervas Chinesas/metabolismo , Panax , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
19.
PLoS One ; 15(5): e0233031, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407356

RESUMO

In order to determine correct dosage of chemotherapy drugs, the effect of the drug must be properly quantified. There are two important values that characterize the effect of the drug: εmax is the maximum possible effect of a drug, and IC50 is the drug concentration where the effect diminishes by half. There is currently a problem with the way these values are measured because they are time-dependent measurements. We use mathematical models to determine how the εmax and IC50 values depend on measurement time and model choice. Seven ordinary differential equation models (ODE) are used for the mathematical analysis; the exponential, Mendelsohn, logistic, linear, surface, Bertalanffy, and Gompertz models. We use the models to simulate tumor growth in the presence and absence of treatment with a known IC50 and εmax. Using traditional methods, we then calculate the IC50 and εmax values over fifty days to show the time-dependence of these values for all seven mathematical models. The general trend found is that the measured IC50 value decreases and the measured εmax increases with increasing measurement day for most mathematical models. Unfortunately, the measured values of IC50 and εmax rarely matched the values used to generate the data. Our results show that there is no optimal measurement time since models predict that IC50 estimates become more accurate at later measurement times while εmax is more accurate at early measurement times.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Antineoplásicos/farmacocinética , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Humanos , Modelos Lineares , Modelos Logísticos , Conceitos Matemáticos , Neoplasias/patologia
20.
Lancet Oncol ; 21(5): e265-e279, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359502

RESUMO

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food-drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food-drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food-drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food-drug interactions and herb-drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.


Assuntos
Antineoplásicos/efeitos adversos , Interações Alimento-Droga , Interações Ervas-Drogas , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Biotransformação , Absorção Gástrica , Humanos , Absorção Intestinal , Fígado/enzimologia , Terapia de Alvo Molecular , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Fatores de Risco
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