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1.
Int J Nanomedicine ; 16: 2597-2613, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833514

RESUMO

Introduction: Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration. Methods: We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX. Results: SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth. Discussion: Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Compostos Nitrosos/química , Paclitaxel/farmacologia , Albumina Sérica Humana/química , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
AAPS PharmSciTech ; 22(3): 96, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33694067

RESUMO

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.


Assuntos
Abietanos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Galactose/administração & dosagem , Neoplasias Hepáticas/metabolismo , Abietanos/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Galactose/farmacocinética , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
3.
J Med Chem ; 64(3): 1346-1361, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33508189

RESUMO

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the N-acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Capsaicina/análogos & derivados , Capsaicina/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Capsaicina/química , Capsaicina/farmacocinética , Humanos
4.
ACS Appl Mater Interfaces ; 13(2): 2988-2996, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33403846

RESUMO

Hollow graphene oxide microcapsules (GOMs) have been widely used in energy, electronics, catalysis, sensing, tissue engineering, and drug loading due to their unique properties. However, it is still a great challenge to prepare GOMs with high quality and in large quantity using a simple method. In this work, we obtained single-component GOMs using the liquid nitrogen cavitation effect, which directed the self-assembly of graphene oxide (GO) debris at the gas-liquid interface. This method avoids the introduction of additional components and removal of templates. The morphology of GOM with wrinkles on its surface was characterized by transmission electron microscopy and scanning electron microscopy. The abundant polar groups of GO microcapsules enabled them to easily disperse in water. Based on this, GOMs have good potential for loading hydrophobic drugs. Subsequently, we used GOMs as carriers to deliver a hydrophobic drug paclitaxel (PTX), which exhibited a good loading capacity. Moreover, PTX loaded GOMs showed excellent cytotoxicity to A549 and MDA-MB-231 cells. The GOMs also showed a pH-dependent drug release performance. Therefore, GOMs can be regarded as potential carriers for biomedical applications.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Portadores de Fármacos/química , Grafite/química , Paclitaxel/administração & dosagem , Células A549 , Antineoplásicos Fitogênicos/farmacocinética , Cápsulas/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Paclitaxel/farmacocinética , Água/química
5.
ACS Appl Mater Interfaces ; 13(4): 4853-4860, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33474938

RESUMO

In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Peptídeos Penetradores de Células/química , Portadores de Fármacos/química , Paclitaxel/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Paclitaxel/farmacocinética , Paclitaxel/farmacologia
6.
Phytomedicine ; 80: 153386, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113500

RESUMO

BACKGROUND: Overexpression of polycomb protein contributes to epigenetic repression in oral squamous cell carcinoma (OSCC) ensuing in poor prognosis and aggressive phenotype. Several plant-based compounds could help prevent epigenome alteration and cancer progression, but their low bioavailability limits their therapeutic activity. HYPOTHESIS: In this study, we have synthesized genistein nanoformulation (GLNPs) and evaluated its epigenetic regulation mechanism for selective apoptosis induction in OSCC. METHODS: Lactalbumin was used to prepare nanoformulation of Genistein. The mechanism of epigenetic regulation and selective apoptosis by Genistein loaded nanoparticles was studied in OSCC cell line JHU011 and fibroblast cell line L929 using immunofluorescence, Western blotting and ChIP-qPCR assay. RESULTS: We have found that GLNPs treatment selectively induced apoptosis in OSCC compared to the normal fibroblast cells. This selective effect in OSCC is achieved through enhanced reactive oxygen species (ROS) generation followed by Bax mitochondrial translocation and caspase 3 activation. Further, GLNPs induced withdrawal of epigenetic transcription repression through concurrent downregulation of the polycomb group proteins (PcG) Bmi 1 and EZH2 along with their successive targets, UbH2AK119 and H3K27me3, which have immense therapeutic implications in the treatment of OSCC. Last, we have established that GLNPs regulate EZH2expression through proteasomal mediated degradation and 3PK inhibition; 3PK protein was found physically linked with EZH2 protein and its promoter region (-1107 to -1002). This event indicates that 3PK might play some crucial role in EZH2 expression and epigenetic control of OSCC. Moreover, the formulation showed improved biodistribution, aqueous dispersibility and enhanced biocompatibility In-vivo. CONCLUSIONS: These results provide evidence that GLNPs may withdraw epigenetic transcriptional repression and selectively induce apoptosis in human oral squamous cell carcinoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Genisteína/farmacologia , Neoplasias Bucais/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Epigênese Genética/efeitos dos fármacos , Genisteína/administração & dosagem , Genisteína/farmacocinética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Nanopartículas/administração & dosagem , Nanopartículas/química , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biomed Pharmacother ; 133: 111059, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378963

RESUMO

Paclitaxel (PTX), a drug widely used in lung cancer, has serious limitations including the development of peripheral neurotoxicity, which may lead to treatment discontinuation and therapy failure. The transport of PTX in large cationic liposomes could avoid this undesirable effect, improving the patient's prognosis. PTX was encapsulated in cationic liposomes with two different sizes, MLV (180-200 nm) and SUV (80-100 nm). In both cases, excellent biocompatibility and improved internalization and antitumor effect of PTX were observed in human and mice lung cancer cells in culture, multicellular spheroids and cancer stem cells (CSCs). In addition, both MLV and SUV with a polyethylene glycol (PEG) shell, induced a greater tumor volume reduction than PTX (56.4 % and 57.1 % vs. 36.7 %, respectively) in mice. Interestingly, MLV-PEG-PTX did not induce either mechanical or heat hypersensitivity whereas SUV-PEG-PTX produced a similar response to free PTX. Analysis of PTX distribution showed a very low concentration of the drug in the dorsal root ganglia (DRG) with MLV-PEG-PTX, but not with SUV-PEG-PTX or free PTX. These results support the hypothesis that PTX induces peripheral neuropathy by penetrating the endothelial fenestrations of the DRG (80-100 nm, measured in mice). In conclusion, our larger liposomes (MLV-PEG-PTX) not only showed biocompatibility, antitumor activity against CSCs, and in vitro and in vivo antitumor effect that improved PTX free activity, but also protected from PTX-induced painful peripheral neuropathy. These advantages could be used as a new strategy of lung cancer chemotherapy to increase the PTX activity and reduce its side effects.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Polietilenoglicóis/química , Células A549 , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Cátions , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Feminino , Gânglios Espinais/efeitos dos fármacos , Humanos , Lipossomos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/toxicidade , Tamanho da Partícula , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Carga Tumoral
8.
Phytomedicine ; 79: 153326, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32992083

RESUMO

BACKGROUND: Lung cancer is the most common and mortal cancer worldwide. Rhodiola rosea L. (RR), a well-known traditional Chinese medicine (TCM), has been turned out to be effective in anti-lung cancer therapy, but its molecular mechanism of action has not been clearly understood. PURPOSE: In this study, we aimed to elucidate the possible molecular mechanism underlying the effect of RR against non-small cell lung cancer (NSCLC) by systems pharmacology. METHODS: The effects of RR on NSCLC were examined in Lewis lung carcinoma (LLC) tumor-bearing mice models. The possible molecular mechanism was unraveled by systems pharmacology, which includes pharmacokinetics evaluation, active compounds screening, target prediction and network analysis. Cell proliferation was examined by cell counting kit-8 (CCK-8) assay; cell apoptosis was detected by flow cytometry; protein and proinflammatory cytokines expression were evaluated by Western blot and qRT-PCR. RESULTS: In vivo, RR significantly inhibited the tumor growth and prolonged the survival of the tumor bearing mice. In silico, we identified 19 potential active molecules (e.g., salidroside and rhodiosin), 112 targets (e.g., COX-2 and AKT) and 27 pathways (e.g., PI3K/AKT signaling pathway and NF-κB signaling pathway) for RR. Additionally, targets analysis and networks construction further revealed that RR exerted anti-cancer effects by regulating apoptosis, angiogenesis and inflammation. In vitro, salidroside could significantly decrease expression of pro-angiogenic factors (e.g., VEGF and eNOS) and proinflammatory cytokines (e.g., COX-2, iNOS and TNF-α). Also, Bcl-2, an anti-apoptotic protein was decreased whereas Bax, a pro-apoptotic protein, was increased. Further flow cytometry analysis showed that salidroside could induce apoptosis in H1975 cells. CONCLUSIONS: Mechanistically, the antitumor effect of RR on NSCLC was responsible for the synergy among anti-inflammatory, anti-angiogenic and pro-apoptotic.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Rhodiola/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucosídeos/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monossacarídeos/farmacologia , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA
9.
Int J Nanomedicine ; 15: 5963-5975, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884259

RESUMO

Background: Previous studies have reported that quercetin (Q) has a potential antibacterial and anticancer activity. However, its application is limited by many important factors including high hydrophobicity and low absorption. Methodology: In the current study, we synthesized and characterized (Patent) a novel chitosan-based quercetin nanohydrogel (ChiNH/Q). Encapsulation efficiency was confirmed by UV/VIS spectrophotometer. Physicochemical characterization of ChiNH/Q was assessed by PDI, DLS, SEM, FTIR, and XRD. The toxicity of the ChiNH/Q against five strains of the pathogen and HepG2 cells was examined. Moreover, the quantification of ChiNH/Q on genomic global DNA methylation and expression of DNMTs (DNMT1/3A/3B) in HepG2 cancer cells were evaluated by ELISA and real-time PCR, respectively. Results: Under the SEM-based images, the hydrodynamic size of the ChiNH/Q was 743.6 nm. The changes in the PDI were 0.507, and zeta potential was obtained as 12.1 mV for ChiNH/Q. The FTIR peak of ChiNH/Q showed the peak at 627 cm-1 corresponded to tensile vibrational of NH2-groups related to Q, and it is the indication of Q loading in the formulation. Moreover, XRD data have detected the encapsulation of ChiNH/Q. The ChiNH/Q showed a potent antimicrobial inhibitory effect and exerted cytotoxic effects against HepG2 cancer cells with IC50 values of 100 µg/mL. Moreover, our data have shown that ChiNH/Q effectively reduced (65%) the average expression level of all the three DNMTs (p<0.05) and significantly increased (1.01%) the 5-methylated cytosine (5-mC) levels in HepG2 cells. Conclusion: Our results showed for the first time the bioavailability and potentiality of ChiNH/Q as a potent antimicrobial and anticancer agent against cancer cells. Our result provided evidence that ChiNH/Q could effectively reduce cellular DNMT expression levels and increase genomic global DNA methylation in HepG2 cancer cells. Our results suggest a potential clinical application of nanoparticles as antimicrobial and anticancer agents in combination cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Hidrogéis/química , Nanoestruturas/química , Quercetina/farmacologia , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Quitosana/química , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Células Hep G2 , Humanos , Hidrogéis/administração & dosagem , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Nanoestruturas/administração & dosagem , Quercetina/administração & dosagem , Quercetina/química , Quercetina/farmacocinética , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
10.
Int J Nanomedicine ; 15: 5073-5082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764937

RESUMO

Objective: To prepare xanthatin (XA)-loaded polydopamine (PDA) nanoparticles (PDA-XA-NPs) and to investigate their adhesion and bioavailability. Materials and methods: PDA-XA-NPs were synthesized and characterized using transmission electron microscopy, zeta potential analysis and encapsulation efficiency analysis. Their in vitro release kinetics and inhibitory effects on gastric cancer were studied. The adhesion of PDA-XA-NPs was evaluated by in vivo imaging atlas. The pharmacokinetics of PDA-XA-NPs and XA was compared. Results: PDA-XA-NPs had a spherical shape, a particle size of about 380 nm, an encapsulation efficiency of (82.1 ± 0.02) % and a drug loading capacity of (5.5 ± 0.1)%. The release of PDA-XA-NPs in PBS was stable and slow, without being affected by pH. The adhesion capacity of PDA-XA-NPs for mucin was significantly higher than that of bulk drug. The gastric mucosal retention of PDA-XA-NPs reached 89.1% which significantly exceeded that of XA. In vivo imaging showed that PDA-XA-NPs targeting the stomach were retained for a period of time. The pharmacokinetics study showed that PDA-XA-NPs had a longer retention time and a slower drug release than those of XA. In vitro experiments confirmed that PDA-XA-NPs exerted similar inhibitory effects on gastric cancer to those of XA, which lasted for a period of time. Conclusion: High-adhesion NPs were constructed. Gastric cancer was targeted by orally administered PDA-XA-NPs, as a potentially feasible therapy. Eventually, the bioavailability of XA was increased.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Furanos/farmacocinética , Nanopartículas/química , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Furanos/química , Mucosa Gástrica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Masculino , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Nanopartículas/metabolismo , Tamanho da Partícula , Polímeros/química , Ratos Sprague-Dawley , Neoplasias Gástricas/patologia
11.
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
12.
Int J Nanomedicine ; 15: 2885-2902, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425522

RESUMO

Purpose: Poor site-specific delivery and insufficient intracellular drug release in tumors are inherent disadvantages to successful chemotherapy. In this study, an extraordinary polymeric micelle nanoplatform was designed for the efficient delivery of paclitaxel (PTX) by combining dual receptor-mediated active targeting and stimuli response to intracellular reduction potential. Methods: The dual-targeted redox-sensitive polymer, folic acid-hyaluronic acid-SS-vitamin E succinate (FHSV), was synthesized via an amidation reaction and characterized by 1H-NMR. Then, PTX-loaded FHSV micelles (PTX/FHSV) were prepared by a dialysis method. The physiochemical properties of the micelles were explored. Moreover, in vitro cytological experiments and in vivo animal studies were carried out to evaluate the antitumor efficacy of polymeric micelles. Results: The PTX/FHSV micelles exhibited a uniform, near-spherical morphology (148.8 ± 1.4 nm) and a high drug loading capacity (11.28% ± 0.25). Triggered by the high concentration of glutathione, PTX/FHSV micelles could quickly release their loaded drug into the release medium. The in vitro cytological evaluations showed that, compared with Taxol or single receptor-targeted micelles, FHSV micelles yielded higher cellular uptake by the dual receptor-mediated endocytosis pathway, thus leading to significantly superior cytotoxicity and apoptosis in tumor cells but less cytotoxicity in normal cells. More importantly, in the in vivo antitumor experiments, PTX/FHSV micelles exhibited enhanced tumor accumulation and produced remarkable tumor growth inhibition with minimal systemic toxicity. Conclusion: Our results suggest that this well-designed FHSV polymer has promising potential for use as a vehicle of chemotherapeutic drugs for precise cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Micelas , Paclitaxel/administração & dosagem , Polímeros/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Ácido Fólico/química , Glutationa/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Células MCF-7 , Camundongos , Terapia de Alvo Molecular , Células NIH 3T3 , Oxirredução , Paclitaxel/farmacocinética , Coelhos , Ensaios Antitumorais Modelo de Xenoenxerto , alfa-Tocoferol/química
13.
Int J Nanomedicine ; 15: 2921-2933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425524

RESUMO

Background: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic. Methods and Results: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects. Conclusion: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Paclitaxel/administração & dosagem , Pró-Fármacos/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fluoresceína-5-Isotiocianato/química , Glucosamina/química , Ácido Glutâmico/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacocinética , Pró-Fármacos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Nanomedicine ; 15: 2337-2349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308385

RESUMO

Purpose: The aim of this study was to develop an "all-in-one" nanoplatform that integrates at the second near-infrared (NIR-II) region dye IR1061 and anticancer drug paclitaxel (PTX) into an apoferritin (AFN) nanocage (IR-AFN@PTX). Simultaneously, folic acid (FA), tumor target molecule,  was conjugated onto IR-AFN@PTX to be IR-AFN@PTX-FA for tumor-targeted and pH/NIR-II-triggered synergistic photothermal-chemotherapy. Methods: IR1061 was firstly reacted with PEG and then conjugated with AFN to be IR-AFN. Then, FA was conjugated onto the surface of IR-AFN to be IR-AFN-FA. At last, PTX was incorporated into IR-AFN-FA to fabricate a nanoplatform IR-AFN@PTX-FA. The NIR-II photothermal properties and pH/NIR-II triggered drug release were evaluated. The ability of IR-AFN@PTX-FA to target tumors was estimated using optical bioluminescence. In vitro and in vivo synergistic therapeutic effects of pH/NIR-II-triggered and tumor-targeted photothermal-chemotherapy were investigated in 4T1 tumor model. Results: IR-AFN@PTX-FA showed excellent water solubility and physiological stability, which significantly enhanced the solubility of both IR1061 and PTX. After 5 min of laser irradiation at 1064 nm, IR-AFN@PTX-FA exhibited an effective photothermal effect compared with laser irradiation at 808 nm, even when blocked with 0.6 cm thick chicken breast. Cellular uptake experiments showed IR-AFN@PTX-FA utilized clathrin-mediated and caveolae-mediated endocytosis pathways to enter 4T1 cells, and was then delivered by the endosome to the lysosome. NIR-II laser irradiation and pH could synergistically trigger PTX release, inducing significant tumor inhibition in vitro and in vivo. Conclusion: As a novel "all-in-one" nanoplatform, IR-AFN@PTX-FA was found to selectively target tumors and showed very efficient NIR-II photothermal effects and pH/NIR-II triggered drug release effects, showing a remarkable, synergistic photothermal-chemotherapy effect.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Boratos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Piranos/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoferritinas/química , Linhagem Celular Tumoral , Corantes/química , Liberação Controlada de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Lasers , Camundongos Endogâmicos BALB C , Nanopartículas/química , Paclitaxel/farmacocinética , Fototerapia/métodos , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Nanomedicine ; 15: 2277-2286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280220

RESUMO

Purpose: In this study, NK4-conjugated hydroxycamptothecin liposomes (NK4-HCPT-Lips) were prepared with the aim of improving drug targeting to the liver. Methods: NK4-HCPT-Lips were prepared using the thin-film dispersion method. In vitro antitumor activities were evaluated by MTT assay. HCPT levels in plasma and tissues were determined via high-performance liquid chromatography (HPLC) with camptothecin as the internal standard, and the characteristics, pharmacokinetics, and bio-distribution of NK4-HCPT-Lips were evaluated. Results: The liposomes showed a regular spherical-shaped morphology, and the entrapment efficiency and drug loading capacity reached 82.5 ± 2.4% and 3.01 ± 0.23%, respectively, with a particle size of 155.6 ± 2.6 nm and a zeta potential of -24.8 ± 3.3 mV. Inhibition effect experiments found that NK4-HCPT-Lips had a good inhibition on the HepG2 cells. Pharmacokinetic studies revealed an increase in the area under the curve and mean residence time as well as a decrease in plasma clearance (p < 0.05) of the NK4-HCPT-Lips compared to those of HCPT liposomes and a commercial HCPT injection. Tissue distribution studies showed that NK4-HCPT-Lips were present at high levels in the liver but were cleared from the kidneys. Conclusion: These results demonstrate that NK4-HCPT-Lips possess excellent liver-targeting attributes, which could enhance the therapeutic effects of drug treatments for hepatic diseases.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Células Hep G2 , Humanos , Interleucinas/química , Rim/efeitos dos fármacos , Rim/metabolismo , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/farmacocinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Tamanho da Partícula , Ratos Sprague-Dawley , Distribuição Tecidual
16.
Int J Nanomedicine ; 15: 1915-1928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32256068

RESUMO

Background: Melanoma is the most common symptom of aggressive skin cancer, and it has become a serious health concern worldwide in recent years. The metastasis rate of malignant melanoma remains high, and it is highly difficult to cure with the currently available treatment options. Effective yet safe therapeutic options are still lacking. Alternative treatment options are in great demand to improve the therapeutic outcome against advanced melanoma. This study aimed to develop albumin nanoparticles (ANPs) coated with macrophage plasma membranes (RANPs) loaded with paclitaxel (PTX) to achieve targeted therapy against malignant melanoma. Methods: Membrane derivations were achieved by using a combination of hypotonic lysis, mechanical membrane fragmentation, and differential centrifugation to empty the harvested cells of their intracellular contents. The collected membrane was then physically extruded through a 400 nm porous polycarbonate membrane to form macrophage cell membrane vesicles. Albumin nanoparticles were prepared through a well-studied nanoprecipitation process. At last, the two components were then coextruded through a 200 nm porous polycarbonate membrane. Results: Using paclitaxel as the model drug, PTX-loaded RANPs displayed significantly enhanced cytotoxicity and apoptosis rates compared to albumin nanoparticles without membrane coating in the murine melanoma cell line B16F10. RANPs also exhibited significantly higher internalization efficiency in B16F10 cells than albumin nanoparticles without a membrane coating. Next, a B16F10 tumor xenograft mouse model was established to explore the biodistribution profiles of RANPs, which showed prolonged blood circulation and selective accumulation at the tumor site. PTX-loaded RANPs also demonstrated greatly improved antitumor efficacy in B16F10 tumor-bearing mouse xenografts. Conclusion: Albumin-based nanoscale delivery systems coated with macrophage plasma membranes offer a highly promising approach to achieve tumor-targeted therapy following systemic administration.


Assuntos
Albuminas/química , Macrófagos/citologia , Melanoma Experimental/tratamento farmacológico , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/química , Feminino , Humanos , Macrófagos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Paclitaxel/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Phytomedicine ; 69: 153183, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32113150

RESUMO

BACKGROUND: Osteosarcoma (OS) is a significant threat to the lives of children and young adults. Although neoadjuvant chemotherapy is the first choice of treatment for OS, it is limited by serious side-effects and cancer metastasis. ß-Elemonic acid (ß-EA), an active component extracted from Boswellia carterii Birdw., has been reported to exhibit potential anti-inflammatory and anticancer activities. However, the anti-tumor effects and underlying mechanisms on OS as well as pharmacokinetic characteristics of ß-EA remain unknown. PURPOSE: This study was aimed to investigating the anti-tumor effects of ß-EA on human OS, the underlying mechanisms, and the pharmacokinetic and tissue distribution characteristics. STUDY DESIGN AND METHODS: Cell viability and colony formation assays were performed to determine the effect of ß-EA cell on cell proliferation. Apoptosis rates, mitochondrial membrane potential and cell cycle features were analyzed by flow cytometry. qRT-PCR, Western blot, immunofluorescence and immunohistochemical assays were conducted to evaluate the expression levels of genes or proteins related to the pathways affected by ß-EA in vitro and in vivo. Cell migration and invasion were evaluated in wound healing and Transwell chamber assays. The effects and pharmacokinetic characteristics of ß-EA in vivo were evaluated by analyzing tumor suppression, pharmacokinetics and tissue distribution. RESULTS: Explorations indicated that endoplasmic reticulum (ER) stress conditions provoked by ß-EA activated the PERK/eIF2α/ATF4 branch of the unfolded protein reaction (UPR), stimulating C/EBP homologous protein (CHOP)-regulated apoptosis and inducing Ca2+ leakage leading to caspase-dependent apoptosis. Furthermore, ß-EA induced G0/G1 cell cycle arrest and inhibited metastasis of HOS and 143B cells by attenuating Wnt/ß-catenin signaling effects, which included decreased levels of p-Akt(Ser473), p-Gsk3ß (Ser9), Wnt/ß-catenin target genes (c-Myc and CyclinD1) along with a decline in nuclear ß-catenin accumulation. The fast absorption, short elimination half-life, and linear pharmacokinetic characteristics of ß-EA were also revealed. The distribution of ß-EA was detected in the tumor and bone tissues. CONCLUSIONS: Overall, both in vitro and in vivo investigations showed the potential of ß-EA for the treatment of human OS. The pharmacokinetic profile and considerable distribution in the tumor and bone tissues warrant further preclinical or even clinical studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Fenantrenos/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Fator de Iniciação 2 em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Distribuição Tecidual , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Triterpenos , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo , eIF-2 Quinase/metabolismo
18.
Int J Nanomedicine ; 15: 553-571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158208

RESUMO

Background: Breast cancer is the leading cause of cancer death in women. Chemotherapy to inhibit the proliferation of cancer cells is considered to be the most important therapeutic strategy. The development of long-circulating PEG and targeting liposomes is a major advance in drug delivery. However, the techniques used in liposome preparation mainly involve conventional liposomes, which have a short half-life, high concentrations in the liver and spleen reticuloendothelial system, and no active targeting. Methods: Four kinds of paclitaxel liposomes were prepared and characterized by various analytical techniques. The long-term targeting effect of liposomes was verified by fluorescence detection methods in vivo and in vitro. Pharmacokinetic and acute toxicity tests were conducted in ICR mice to evaluate the safety of different paclitaxel preparations. The antitumor activity of ES-SSL-PTX was investigated in detail using in vitro and in vivo human breast cancer MCF-7 cell models. Results: ER-targeting liposomes had a particle size of 137.93±1.22 nm and an acceptable encapsulation efficiency of 88.07±1.25%. The liposome preparation is best stored at 4°C, and is stable for up to 48 hrs. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. We used the near-infrared fluorescence imaging technique to confirm that ES-SSL-PTX was effectively targeted and could quickly and specifically identify the tumor site. Pharmacokinetics and acute toxicity in vivo experiments were carried out. The results showed that ES-SSL-PTX could significantly prolong the half-life of the drug, increase its circulation time in vivo, improve its bioavailability and reduce its toxicity and side effects. ES-SSL-PTX can significantly improve the pharmacokinetic properties of paclitaxel, avoid allergic reaction of the original solvent, increase antitumor efficacy and reduce drug toxicity and side effects. Conclusion: ES-SSL-PTX has great potential for improving the treatment of breast cancer, thereby improving patient prognosis and quality of life.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/farmacocinética , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Meia-Vida , Humanos , Lipossomos/química , Lipossomos/toxicidade , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Paclitaxel/administração & dosagem , Paclitaxel/toxicidade , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Biomater Sci ; 8(8): 2274-2282, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162618

RESUMO

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Cumarínicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Peptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tiazóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos ICR , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/química , Esferoides Celulares/efeitos dos fármacos , Tiazóis/química , Carga Tumoral/efeitos dos fármacos
20.
Drug Deliv ; 27(1): 248-257, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32003255

RESUMO

Cancer is a kind of malignant diseases that threatens human health and the research application of anti-tumor drug therapeutics is growingly always been focused on. Many new compounds with great anticancer activity were synthesized but cannot be hard to be developed into clinical use due to its poor water solubility. Deoxypodophyllotoxin (DPT) is just an example. We develop lyophilized Deoxypodophyllotoxin (DPT) loaded polymeric micelles using methoxy polyethylene glycol-block-Poly (D, L-lactide) (mPEG-PLA). DPT-PM freeze-dried powder was successfully prepared using optimized formulation. mPEG-PLA was added to hydration media before hydrating as cryoprotectants. The freeze-dried powder exhibited white pie-solid without collapsing, and the particle size of DPT-PM reconstituted with water was about 20-35 nm. The entrapment efficiency of the reconstituted solution was 98%, which shows no differences with the micelles before lyophilization. In-vitro cytotoxicity and cellular uptake studies showed that DPT-PM has a higher degree of cytotoxicity comparing with DPT and mPEG-PLA micelles and uptake of mPEG-PLA was concentration and time-dependent. In vivo characterization of DPT-PM was done for pharmacokinetics behaviors, antitumor activity and safety. The obtained results showed significant improvement in plasma clearance bioavailability (p <0.05) and prolonged blood circulation time comparing with DPT-HP-ß-CD. Moreover, mPEG-PLA micelles had a better degree of anti-tumor efficacy, this was due to better accumulation of mPEG-PLA in tumor cell via enhanced permeability and retention (EPR) effect. Therefore, DPT-PM has great clinical value, and can be expected to be a novel antitumor preparation.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Nanopartículas , Podofilotoxina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Liofilização , Humanos , Masculino , Camundongos , Camundongos Nus , Micelas , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Podofilotoxina/administração & dosagem , Podofilotoxina/farmacocinética , Podofilotoxina/farmacologia , Poliésteres/química , Polietilenoglicóis/química , Fatores de Tempo , Distribuição Tecidual
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