RESUMO
Folic acid (FA) has been widely engineered to promote the targeted delivery of FA-modified nanoparticles (NPs) by recognizing the folate receptor α (FRα). However, the efficacy of FA-targeted therapy significantly varied with the abundance of FRα and natural immunoglobulin levels in different tumors. Therefore, a sequential therapy of dexamethasone (Dex)-induced FRα amplification and immunosuppression combined with FA-functionalized doxorubicin (DOX) micelles to synergistically suppress tumor proliferation was proposed in this study. In brief, a pH/reduction-responsive FA-functionalized micelle (FCSD) was obtained by grafting FA, derivatization-modified cholesterol, and 2,3-dimethylmaleic anhydride onto a chitosan oligosaccharide. The obtained FCSD/DOX NPs can effectively deliver DOX in tumors, and their targeting efficiency can be further improved with Dex pretreatment to decrease the immunoglobulin M (IgM) content in serum and amplify FRα levels on the surface of M109 cells. After internalization, charge reversal and disulfide bond breakage of FCSD vectors under the stimulation of tumor extracellular pH (pHe) and intracellular glutathione (GSH) would contribute to the disintegration of vectors and the rapid release of DOX. The sequential therapy that combined Dex pretreatment and targeted chemotherapy by FCSD/DOX NPs demonstrated superior tumor suppression compared with monotherapy, which is expected to provide a potential strategy for FRα-positive lung cancer patients.
Assuntos
Neoplasias Pulmonares , Nanopartículas , Humanos , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamento farmacológico , Ácido Fólico/química , Doxorrubicina , Micelas , Nanopartículas/química , Dexametasona , Sistemas de Liberação de Medicamentos , Concentração de Íons de HidrogênioRESUMO
Although gene therapy has shown prospects in treating triple-negative breast cancer, it is insufficient to treat such a malignant tumor. Herein, nanoparticles (NPs)-embedded dissolving microneedles (IR780-PL/pFBXO44@MNs) with steerable and flectional property were developed to achieve the codelivery of FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and hydrophobic photosensitizers. For improved NP penetration in tumor tissue, collagenase@MNs were preapplied to degrade the tumor matrix. Under light irradiation, IR780 exhibited remarkable phototherapy, while the escape efficiency of NPs from lysosomes was improved. pFBXO44 was subsequently released in tumor cell cytoplasm via reducing the disulfide bonds of NPs, which could specifically knock out the FBXO44 gene to inhibit the migration and invasion of tumor cells. As a result, tumor cells were eradicated, and lung metastasis was effectively suppressed. This micelle-incorporated microneedle platform broadens the potential of combining gene editing and photo synergistic cancer therapy.
Assuntos
Neoplasias , Fármacos Fotossensibilizantes , Sistemas CRISPR-Cas/genética , Terapia Combinada , Fototerapia , LisossomosRESUMO
In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss-polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like receptor 4 siRNA (TLR4-siRNA) and doxorubicin (Dox). In vitro investigation revealed the sustained gene and drug release from Dox-siRNA-loaded micelles under physiological conditions, and this codelivery nanosystem exhibited high dual pH/redox sensitivity, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Furthermore, the micelles loaded with TLR4-siRNA inhibited the migration and invasion of A549. Excellent tumor penetrating efficacy was also noted in the A549 tumor spheroids and solid tumor slices. In vivo, multiple results demonstrated the excellent tumor-targeting ability of AS1411-chitosan-ss-polyethylenimine-urocanic acid (ACPU) micelle in tumor tissues. The micelles exhibited excellent antitumor efficacy and low toxicity in the systemic circulation in lung-tumor-bearing BALB/c mice. These results conclusively demonstrated the great potential of the new graft copolymer micelle with targeting function for the targeted and efficient codelivery of chemotherapeutic drugs and genes in cancer treatment.
Assuntos
Micelas , Fosfoproteínas/metabolismo , Polímeros/química , Proteínas de Ligação a RNA/metabolismo , Células A549 , Animais , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Camundongos , Fosfoproteínas/química , RNA Interferente Pequeno , Proteínas de Ligação a RNA/química , NucleolinaRESUMO
cRGD-carboxymethyl chitosan-palmitic acid (cRGD-CMCh-PA) was synthesized and a pH- sensitive paclitaxel-loaded cRGD-CMCh-PA micellesï¼PTX-cRGD-CMCh-PAï¼ was prepared with the film dispersion method; related substances were characterized by FT-IR and (1)H NMR. PTX-cRGD-CMCh-PA micelles were studied with the particle size distribution, zeta potential, morphology and release behavior in vitro was investigated by the method of equilibrium dialysis. In vitro cytotoxicity of different formulations on A549 cells was tested by MTT assay. The uptake process of micelles was explored using confocal microscopy and a live cell station was used to observe the dynamic phagocytosis. The subcutaneous and orthotropic tumor models were built to study the distribution of Di R-labeled micelles by near-infrared fluorescenceï¼NIRï¼ imaging system. The FT-IR spectra and (1)H NMR spectra confirmed the successful conjugation of cRGD-CMCh-PA polymer and the degree of carboxymethyl and the palmitic acid grafted on chitosan were 45.0% and 15.0%. PTX-cRGD-CMCh-PA micelles were prepared with particle size ofï¼162.9 ± 1.5ï¼ nm, zeta potential of +26.3 m V and encapsulation efficiency and the drug loading of 99.67% and 28.5%, respectively. The micelles released slowly in pH 7.4 whose release curves were accorded with the Higuchi equation; they had an initial burst effect in second hours and showed a pH sensitive release behavior in pH 5.3. The IC(50) of PXT-CMCh-PA and PTX-cRGD-CMCh-PA were 2.077 µg·mL(-1) and 0.876 µg·mL(-1), respectively. The cells uptake process of micelles in A549 cells revealed that the micelles were mainly co-located with lysosome and PTX-cRGD-CMCh- PA showed much better targeting effect. The NIR fluorescence imaging results showed that the micelles had a good targeting effect on both subcutaneous and orthotropic tumors. In this study, a novel copolymer cRGD- CMCh-PA was synthesized with a sustained and pH-dependent drug release activity which would potentially become a new carrier for hydrophobic drugs.
Assuntos
Quitosana/análogos & derivados , Portadores de Fármacos/química , Oligopeptídeos/química , Paclitaxel/administração & dosagem , Ácido Palmítico/química , Células A549 , Antineoplásicos Fitogênicos/administração & dosagem , Quitosana/química , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Micelas , Tamanho da Partícula , Polímeros , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Dioscin is a natural steroid saponin derived from several plants, showing potent anti-cancer effect against a variety of tumor cell lines. In the present study, we investigated the anti-cancer activity of dioscin against human LNCaP cells, and evaluated the possible mechanism involved in its antineoplastic action. It was found that dioscin (1, 2 and 4 µmol/L) could significantly inhibit the viability of LNCaP cells in a time- and concentration-dependent manner. Flow cytometry revealed that the apoptosis rate was increased after treatment of LNCaP cells with dioscin for 24 h, indicating that apoptosis was an important mechanism by which dioscin inhibited cancer. Western blotting was employed to detect the expression of caspase-3, Bcl-2 and Bax in LNCaP cells. The expression of cleaved caspase-3 was significantly increased, and meanwhile procaspase-3 was markedly decreased. The expression of anti-apoptotic protein Bcl-2 was down-regulated, whereas the pro-apoptotic protein Bax was up-regulated. Moreover, the Bcl-2/Bax ratio was drastically decreased. These results suggested that dioscin possessed potential anti-tumor activity in human LNCaP cells through the apoptosis pathway, which might be associated with caspase-3 and Bcl-2 protein family.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Diosgenina/análogos & derivados , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/química , Diosgenina/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Citometria de Fluxo , Humanos , Masculino , Estrutura Molecular , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Tempo , Proteína X Associada a bcl-2/metabolismoRESUMO
Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells is exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, Western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggesting that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed the activation of mTOR and p70S6K via the Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design a promising antitumor agent.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pironas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Western Blotting , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Microscopia Eletrônica de TransmissãoRESUMO
The aim of this study was to investigate the neuroprotective effects of (2S)-5, 2', 5'-trihydroxy-7-methoxyflavanone (TMF), a natural product from Abacopteris penangiana (Hook.) Ching, in oxidative stress-induced neurodegeneration models in vitro and in vivo. In PC12 cells, preincubation of TMF (3-20 µM) for 24 h decreased the dopamine-induced toxicity and attenuated the redox imbalance in PC12 cells through regulating the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG), which is a sensitive marker of oxidative stress. Additionally, long-term intraperitoneal (i.p.) injection of TMF (4 or 8 mg/kg/day) for 2 weeks significantly improved the behavioral performance of D-galactose (D-gal) treated mice in a Morris water maze test. Biochemical analysis revealed that TMF inhibited the activation of AP-1 (activator protein-1) and upregulated the level of BDNF (brain derived neurophic factor) as well as the ratio of GSH/GSSG in the hippocampus of D-gal treated mice. Furthermore, western blotting analysis indicated that TMF increased phosphorylation of cAMP-response element-binding protein (CREB). Therefore, the natural product TMF possessed a potential for the treatment of neurodegenerative diseases.
Assuntos
Flavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Pteridaceae/química , Animais , Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Ensaio de Imunoadsorção Enzimática , Flavonas/isolamento & purificação , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , RatosRESUMO
The efficacy of immune checkpoint therapy is limited by the immunosuppressive tumor microenvironment (TME), and lactate, the most universal component of TME, has been rediscovered that plays important roles in the regulation of metabolic pathways, angiogenesis, and immunosuppression. Here, a therapeutic strategy of acidity modulation combined with programmed death ligand-1 (PD-L1) siRNA (siPD-L1) is proposed to synergistically enhance tumor immunotherapy. The lactate oxidase (LOx) is encapsulated into the hollow Prussian blue (HPB) nanoparticles (NPs) prepared by hydrochloric acid etching followed by the modification with polyethyleneimine (PEI) and polyethylene glycol (PEG) via sulfur bonds (HPB-S-PP@LOx), siPD-L1 is loaded via electrostatic adsorption to obtain HPB-S-PP@LOx/siPD-L1. The obtained co-delivery NPs can accumulate in tumor tissue with stable systemic circulation, and simultaneous release of LOx and siPD-L1 in intracellular high glutathione (GSH) environment after uptake by tumor cells without being destroyed by lysosome. Moreover, LOx can catalyze the decomposition of lactate in the hypoxic tumor tissue with the aid of oxygen release by the HPB-S-PP nano-vector. The results show that the acidic TME regulation via lactate consumption can improve the immunosuppressive TME, including revitalizing the exhausted CD8+ T cells and decreasing the proportion of immunosuppressive Tregs, and synergistically elevating the therapeutic effect of PD1/PD-L1 blockade therapy via siPD-L1. This work provides a novel insight for tumor immunotherapy and explores a promising therapy for triple-negative breast cancer.
Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Terapia de Imunossupressão , Imunoterapia/métodos , Lactatos , Microambiente TumoralRESUMO
N-Trimethyl chitosan (TMC) was synthesized and used to prepare lactosyl-norcantharidin TMC nanoparticles (Lac-NCTD-TMC-NPs) using an ionic cross-linkage process. Lac-NCTD-TMC-NPs with an average particle size of 120.6 ± 1.7 nm were obtained, with an entrapment efficiency of 69.29% ± 0.76%, and a drug-loading amount of 9.1% ± 0.07%. The release of Lac-NCTD-TMC-NPs in vitro was investigated through a dialysis method, and its sustained effect was evident. In the human liver cancer cell line HepG2, the half-maximum inhibiting concentration (IC(50)) of TMC-encapsulated Lac-NCTD (Lac-NCTD-TMC-NPs) was only 24.2% that of free Lac-NCTD at 24 hours. Lac-NCTD induced HepG2 cell death by triggering apoptosis. In vitro cellular uptake and in vivo NIR fluorescence real-time imaging both indicated a high targeting efficacy. In comparison with Lac-NCTD and Lac-NCTD chitosan NPs (Lac-NCTD-CS-NPs ), Lac-NCTD-TMC-NPs had the strongest antitumor activity on the murine hepatocarcinoma 22 subcutaneous model. FROM THE CLINICAL EDITOR: In this article the preparation of N-trimethyl chitosan-encapsulated lactosyl-norcantharidin nanoparticles is described that displayed efficient targeting and sustained release in a hepatocarcinoma SC murine model.
Assuntos
Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Quitosana/química , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Nanopartículas/químicaRESUMO
The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration. The renal hypertensive models were established by the two-kidney, one-clip (2K1C) method in Wistar rats. Four weeks later, assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups: racemic TJ0711 10, 20 and 40 mg x kg(-1) groups, carvedilol control group, model group and sham group (n=10), ig administration once daily. The changes of BP (blood press) and HR (heart rate) before and after administration were measured by tail-cuff method weekly. Plasma samples of all animals were taken in 6-8 weeks, and plasma MDA as well as renin, angiotensin II (Ang II) and endothelin-1 (ET-1) levels were measured. Left ventricle was cut off after 9 weeks, and left ventricular weight index (LVWI) and hydroxyproline were measured. The significant decrease of the BP of TJ0711 40 mg x kg(-1) group was observed after TJ0711 ig administration for 4 weeks, and this effect remained till the end of the study. In 8th week, the systolic blood pressure values were: TJ0711 40 mg x kg(-1) group 18.93 +/- 1.82 kPa (vs 21.30 +/- 2.30 kPa, P < 0.05); 20 mg x kg(-1) group 20.68 +/- 3.29 kPa (vs 22.19 +/- 2.88 kPa). The plasma MDA level of all treated groups was significantly lower than that of model group, so were the plasma renin, Ang II and ET-1 levels (P < 0.05). LVWI and hydroxyproline content of myocardial tissue decreased to some extent, but was not significant as compared with that of model group. The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration; besides block adrenal alpha and beta receptors to play an antihypertensive role. The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA. These effects benefited cardiovascular protection.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renal/fisiopatologia , Fenoxipropanolaminas/farmacologia , Angiotensina II/sangue , Animais , Anti-Hipertensivos/administração & dosagem , Endotelina-1/sangue , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hidroxiprolina/metabolismo , Hipertensão Renal/sangue , Estudos Longitudinais , Masculino , Malondialdeído/sangue , Tamanho do Órgão/efeitos dos fármacos , Fenoxipropanolaminas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Renina/sangueRESUMO
Metastatic cancers and recurrent cancers are diverse, different from primary cancers, and organ-dependent. However, how strong are across-cancer immune responses among different types of cancers remain unclear. Herein, vaccines-encapsulated-whole-components-of-tumor-tissue (VEWCOTT) were applied to demonstrate the across-cancer immune responses, thanks to inducing pan-clones T-cell immune responses. Either lung-cancer-tissue- or melanoma-tissue-based VEWCOTT simultaneously prevented melanoma, lung cancer, hepatoma, and metastatic cancer, which showed that strong across-cancer immune responses were induced. Both nanovaccines and microvaccines showed potent across-cancer prevention efficacy. VEWCOTT induced tumor-specific T cells in peripheral immune organs and major organs, and adjusted the immune-microenvironment of cancer-colonized organs. In addition, the allograft of T cells from VEWCOTT immunized mice to allogeneic naive mice efficiently prevent various cancers. Many neoantigens are shared by melanoma cells and lung cancer cells. Across-cancer immune responses exist among different types of cancers, and thus VEWCOTT has the advantage of simultaneously preventing cancer metastasis and cancers in different organs.
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Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system adapted from bacteria is a programmable nuclease-based genome editing tool. The long-lasting effect of gene silencing or correction is beneficial in cancer treatment. Considering the need to broaden the practical application of this technology, highly efficient non-viral vectors are urgently required. We prepared a multifunctional non-viral vector that could actively target tumor cells and deliver CRISPR/Cas9 plasmids into nuclei of cancer cells. Protamine sulfate (PS) which contains nuclear localization sequence was utilized to condense plasmid DNA and facilitate nuclei-targeted delivery. Liposome-coated protein/DNA complex avoided the degradation of nuclease in blood circulation. The obtained PS@Lip/pCas9 was further modified with distearoyl phosphoethanolamine-polyethylene glycol-hyaluronic acid (HA) to endow the vector ability to actively target tumor cell. Results suggested that PS@HA-Lip could deliver CRISPR/Cas9 plasmids into nuclei of tumor cells and induce genome editing effect. With the disruption of MTH1 (mutT homolog1) gene, the growth of non-small cell lung cancer was inhibited. Moreover, cell apoptosis in tumor tissue was promoted, and liver metastasis of non-small cell lung cancer (NSCLC) was reduced. Our study has provided a therapeutic strategy targeting MTH1 gene for NSCLC therapy. STATEMENT OF SIGNIFICANCE: CRISPR/Cas9 as a powerful tool for genome editing has drawn much attention. The long-lasting effect possesses unique advantage in cancer treatment. Non-viral vectors have high loading capacity, high safety and low immunogenicity, playing an important role in CRISPR/Cas9 delivery. In our study, a multifunctional non-viral vector for the efficient delivery of CRISPR/Cas9 plasmid was constructed. With the active targeting ligand and nuclei-targeting component, the cargo was efficiently delivered into cell nuclei and exerted genome editing effect. By using this vector, we successfully inhibited the growth and induced the apoptosis of non-small cell lung cancer by disrupting MTH1 expression with good safety. Our work provided an efficient non-vial vector for CRISPR/Cas9 delivery and explored the possibility for cancer treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Vetores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Edição de Genes/métodos , DNARESUMO
Objectives: Cisplatin (CDDP) is a highly effective chemotherapeutic agent, but its clinical application has been limited by nephrotoxicity. Tanshinone â (T-I), a phenanthrenequinone compound extracted from the Chinese herb Danshen, has been used to improve circulation and treat cardiovascular diseases. The aim of this study was to investigate the protective effect of T-I on CDDP-induced nephrotoxicity in mice. Materials and Methods: The BALB/c mouse models of nephrotoxicity were established by a single intraperitoneal injection of 20 mg/kg CDDP on the first day of the experiment. Three hours prior to CDDP administration, the mice were dosed with 10 mg/kg and 30 mg/kg T-I for 3 consecutive days intraperitoneally to explore nephroprotection of T-I. Results: Treatment with T-I significantly reduced blood urea nitrogen and creatinine levels in serum observed in CDDP-administered mice, especially at a dose of 30 mg/kg. T-I at 30 mg/kg significantly decreased malondialdehyde levels and increased glutathione levels and the enzymatic activity of catalase in kidney tissue compared to CDDP. Additionally, T-I (30 mg/kg) significantly reversed the CDDP-decreased expression level of superoxide dismutase 2 protein in renal tissue. Histopathological evaluation of the kidneys further confirmed the protective effect of T-I. Conclusion: The findings of this study demonstrate that T-I can protect against CDDP-induced nephrotoxicity through suppression of oxidative stress.
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Tumor-sensitivity, effective transport, and precise delivery to tumor cells of nano drug delivery systems (NDDs) have been great challenges to cancer therapy in recent years. The conventional targeting approach involves actively installing the corresponding ligand on the nanocarriers, which is prone to recognize the antigen blasts overexpressed on the surface of tumor cells. However, there are some probable limitations for the active tumor-targeting systems in vivo as follows: a. the limited ligand amount of modifications; b. possible steric hindrance, which was likely to prevent ligand-receptor interaction during the delivery process. c. the restrained antigen saturation highly expressed on the cell membrane, will definitely decrease the specificity and often lead to "off-target" effects of NDDs; and d. water insolubility of nanocarriers due to excess of ligands modification. Obviously, any regulation of receptors on surface of tumor cells exerted an important influence on the delivery of targeting systems. Herein, receptor upregulation was mostly desired for enhancing targeted therapy from the cellular level. This technique with the amplification of receptors has the potential to enhance tumor sensitivity towards corresponding ligand-modified nanoparticles, and thereby increasing the effective therapeutic concentration as well as improving the efficacy of chemotherapy. The enhancement of positively expressed receptors on tumor cells and receptor-dependent therapeutic agents or NDDs with an assembled "self-promoting" effect contributes to increasing cell sensitivity to NPs, and will provide a basic platform for clinical therapeutic practice. In this review, we highlight the significance of modulating various receptors on different types of cancer cells for drug delivery and therapeutic benefits.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Antineoplásicos/uso terapêutico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Lactate, as the most abundant component with concentrations of 4-40 mm in tumors, contributes to the regulation of metabolic pathways, angiogenesis, and immunosuppression, exhibiting remarkable potential in cancer treatment. Therefore, a codelivery strategy that combined the cascaded enzymes Lactate oxidase/Catalase (LOx/CAT) and vascular endothelial growth factor (VEGF) siRNA (siVEGF) to suppress tumor proliferation and angiogenesis synergistically is creatively proposed. In brief, the cationic liposomes (LIP) encapsulated with LOx/CAT and siVEGF via hydrophilic interaction and electrostatic adsorption followed by coating with PEGylated phenylboronic acid (PP) is established (PPL@[LOX+CAT]). Moreover, a simple 3-aminophenylboronic acid (PBA)-shielded strategy via fructose (Fru) is applied to further enhance the targeting efficiency in the tumor site. The obtained co-encapsulated nanoparticles (NPs) can simultaneous intracellular release of LOx/CAT and siVEGF, and the collaborative use of LOx and CAT can promote lactate consumption even under a hypoxic tumor microenvironment (TME) without producing systemic toxicity. The combined application of lactate depletion and VEGF silencing demonstrated the efficient migration suppression of 4T1 cells in vitro and superior antitumor and antimetastatic properties in vivo. This work offers a promising tumor treatment strategy via integrating cascaded enzymes and gene therapy, and explores a promising therapy regimen for 4T1 triple-negative breast cancer.
Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Ácido Láctico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Acute myeloid leukemia (AML) is the most universal type and fatal disease of hematological malignancy, with poor outcomes despite chemotherapy and bone marrow transplantations. Benefited from the narrow tissue specificity of folate receptor ß (FRß) aberrantly expressed on hematological linage cell lines, NPs modified with folate acid (FA) has been widely applied for crossing cell membrane barriers in FR-targeted therapies for AML. Thus, the biomimetic nanoparticles (NPs) mediated by FRß were conducted by an albumin modifier as previously synthesized and cationic liposomes. However, how to further enhance the tumor-targeting and cellular uptake of NPs have been great challenges in cancer therapy. It was reported that FRß could be selectively augmented by all-trans retinoic acid (ATRA). Herein, we demonstrated the enhanced active tumor-targeting of FA-modified siRNA-loaded biomimetic albumin NPs (Lip-S@FBH) could be achieved by upregulating FRß expression via ATRA NPs. And the systematic administration of ATRA NPs significantly promoted endocytosis and thereby increased the intracellular concentration of Lip-S@FBH. This strategy combined the FRß amplification effect with the effective delivery of siRNA, is mostly desirable for the AML-targeting therapy.
Assuntos
Sistemas de Liberação de Medicamentos , Receptor 2 de Folato , Leucemia Mieloide Aguda/tratamento farmacológico , Nanopartículas , Tretinoína , Albuminas , Biomimética , Ácido Fólico , Humanos , RNA Interferente Pequeno , Tretinoína/farmacologiaRESUMO
The continuous activation and expansion of tumor-specific T cells by various means are the main goal of cancer immunotherapy. Tumor cells overexpress fibrinogen-like protein 1 (FGL1) and programmmed death-ligand 1 (PD-L1), which respectively bind to lymphocyte-activation gene 3 (LAG-3) and programmmed death-1(PD-1) on T cells, forming important signaling pathways (FGL1/LAG-3 and PD-1/PD-L1) that negatively regulate immune responses. In order to interfere with the inhibitory function of FGL1 and PD-L1 proteins, we designed a new type of reactive oxygen species (ROS)-sensitive nanoparticles to load FGL1 siRNA (siFGL1) and PD-L1 siRNA (siPD-L1), which was formed from a stimuli-responsive polymer with a poly-l-lysine-thioketal and modified cis-aconitate to facilitate endosomal escape. Moreover, tumor-penetrating peptide iRGD and ROS-responsive nanoparticles were co-administered to further enhance the delivery efficiency of siFGL1 and siPD-L1, thereby significantly reducing the protein levels of FGL1 and PD-L1 in tumor cells. Our findings indicated that the dual delivery of FGL1/PD-L1 siRNA was a new and powerful treatment method, which was characterized by increasing the infiltration of effector CD4+ and CD8+ T cells, effectively alleviating the tumor immunosuppressive microenvironment. These findings also supported the superiority and feasibility of nanoparticle-mediated tumor immunotherapy, and may provide a different perspective for cancer treatment. STATEMENT OF SIGNIFICANCE: In addition to the idea that cancer vaccines can promote T cell immune responses, nanoparticle delivery modulators (such as small interfering RNA (siRNA) targeting immunosuppressive pathways) may provide more information for the research of nanoparticle-mediated cancer immunotherapy. In this study, we designed a new intelligent nano-delivery system for co-delivery of siFGL1 and siPD-L1, and demonstrated the ability to down-regulate the expression levels of FGL1 and PD-L1 proteins in tumor cells in vitro and in vivo. The constructed nanoparticle had a good tumor microenvironment responsiveness, and the delivery efficiency was enhanced by co-injection with tumor penetrating peptide iRGD. This project proposed a new strategy for tumor immunotherapy based on smart nano-delivery systems, and explored more possibilities for tumor therapy.
Assuntos
Antígeno B7-H1 , Fibrinogênio/administração & dosagem , Nanopartículas , Oligopeptídeos/uso terapêutico , Animais , Antígeno B7-H1/administração & dosagem , Linhagem Celular Tumoral , Imunoterapia , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Tumor tissues/cells are the best sources of antigens to prepare cancer vaccines. However, due to the difficulty of solubilization and delivery of water-insoluble antigens in tumor tissues/cells, including water-insoluble antigens into cancer vaccines and delivering such vaccines efficiently to antigen-presenting cells (APCs) remain challenging. To solve these problems, herein, water-insoluble components of tumor tissues/cells are solubilized by 8 m urea and thus whole components of micrometer-sized tumor cells are reasssembled into nanosized nanovaccines. To induce maximized immunization efficacy, various antigens are loaded both inside and on the surface of nanovaccines. By encapsulating both water-insoluble and water-soluble components of tumor tissues/cells into nanovaccines, the nanovaccines are efficiently phagocytosed by APCs and showed better therapeutic efficacy than the nanovaccine loaded with only water-soluble components in melanoma and breast cancer. Anti-PD-1 antibody and metformin can improve the efficacy of nanovaccines. In addition, the nanovaccines can prevent lung cancer (100%) and melanoma (70%) efficiently in mice. T cell analysis and tumor microenvironment analysis indicate that tumor-specific T cells are induced by nanovaccines and both adaptive and innate immune responses against cancer cells are activated by nanovaccines. Overall, this study demonstrates a universal method to make tumor-cell-based nanovaccines for cancer immunotherapy and prevention.
Assuntos
ImunoterapiaRESUMO
In this study a new chitosan (CS) derivative, galactosylated chitosan (GC), was synthesized and used to prepare norcantharidin-associated GC nanoparticles (NCTD-GC NPs) by taking advantage of the ionic cross-linkage between the molecules of the anti-hepatocarcinoma medicine NCTD and of the GC as carrier. NCTD-GC NPs were obtained with average particle size of 118.68 +/- 3.37 nm, entrapment efficiency of 57.92 +/- 0.40%, and drug-loading amount of 10.38 +/- 0.06%. Several important factors influencing the entrapment efficiency, drug-loading amount, and particle size of NCTD-GC NPs were studied. The characteristics of sustained and pH-sensitive release of NCTD from NCTD-GC NPs in vitro were studied. In addition, in vitro cellular uptake and cytotoxicity of nanoparticles to hepatoma cell lines SMMC-7721 and HepG2 were also investigated. In vitro, and compared to CS-based NCTD-CS NPs, NCTD-GC NPs demonstrated satisfactory compatibility with hepatoma cells and strong cytotoxicity against hepatocellular carcinoma cells. In vivo antitumor activity of NCTD-GC NPs was evaluated in mice bearing H22 liver tumors. NCTD-GC NPs displayed tumor inhibition effect in mice, better than either the free NCTD or the NCTD-CS NPs. As a hepatocyte-targeting carrier, GC NPs are potentially promising for clinical applications. FROM THE CLINICAL EDITOR: In this paper, a galactosylated chitosan (GC), was synthesized and norcantharidin (NCTD)-associated galactosylated chitosan nanoparticles (NCTDGC NPs) were generated by coupling NCTD--an anti-hepatocarcinoma drug--and GC as carrier. Compared to chitosan nanoparticles, NCTD-GC-NPs demonstrated satisfactory compatibility with hepatoma cells and strong cytotoxicity against the cells.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Carcinoma Hepatocelular/tratamento farmacológico , Quitosana/química , Portadores de Fármacos/química , Galactose/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/uso terapêutico , Animais , Carcinoma Hepatocelular/diagnóstico , Linhagem Celular Tumoral , Neoplasias Hepáticas/diagnóstico , Camundongos , Nanopartículas/químicaRESUMO
How to overcome the cell membrane barriers and achieve release payloads efficiently in the cytoplasm have been major challenges for anticancer drug delivery and therapeutic effects with nanosystems. In this study, bovine serum albumin (BSA) was modified with folate acid and histamine, which was then used as the nanocarrier for the antitumor agent doxorubicin (DOX). The DOX-loaded nanoparticles (DOX/FBH-NPs) were prepared via a crosslinking method, and the release of DOX from these nanoparticles (NPs) exhibited pH/reduction-responsive behaviors in vitro. These NPs interacted with the folate receptor overexpressed on the cell membrane of 4 T1 cells and achieved enhanced endocytosis. Afterwards, these NPs exhibited pH-responsiveness within endo-lysosomes and escaped from endosomes due to the "proton sponge" effect, and then completed release of DOX was triggered by high concentration of glutathione (GSH) in cytoplasm. Thus, DOX/FBH-NPs exhibited excellent cytotoxicity against 4 T1 cells in vitro. Benefited from the enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis, these NPs gained satisfied tumor-targeting effects in vivo and efficient delivery of DOX to tumor tissues. As a result, these NPs exhibited enhanced antitumor effects and reduced side effects in vivo. In conclusion, these BSA-based NPs modified with both folate acid and histamine showed enhanced tumor-targeting effects in vivo with good biocompatibility and intracellular pH/reduction-responsive behaviors, providing a promising strategy for the efficient delivery of antitumor agents.