Abstract:Multidrug resistance (MDR) and lack of targeting specificity are the main reasons why traditional drug therapies fail and produce toxic side effects in cancer chemotherapy. In order to increase targeting specificity and maximize therapeutic efficacy, new intelligent drug delivery systems are needed. In this study, we prepared the hyaluronic acid (HA) conjugated dasatinib (DAS) and D-α-tocopherol acid polyethylene glycolsuccinate (TPGS) copolymer nanoparticles (THD-NPs). The water solubility of the hydrophobic … Show more
“…As shown in Figure 6A and B , the accumulation of DAS and OLA in the HDO-NPs group was higher than that in the free DAS + OLA group at each time point, owing to the introduction of hyaluronic acid, which could be better taken up by tumor cells and increase drug endocytosis. 38 Meanwhile, the drug accumulations in the HA blocking group were lower than that in the HDO-NPs group, which also reflected the above conjecture, further showing that the targeting of HA can enhance the accumulation of drugs in cells. Figure 6 The accumulation of ( A ) DAS and ( B ) OLA in MDA-MB-231 cells incubated with DAS + OLA, HA + HDO-NPs and HDO-NPs for different times.…”
Section: Resultssupporting
confidence: 52%
“…HDO-NPs were hydrolyzed by strong alkaline hydrolysis to determine the drug loading and encapsulation efficiency of DAS and OLA. 37 , 38 In short, 4 mg HDO-NPs were dissolved in 1 mL deionized water, 100 μL NaOH (1 mol/L) was added for 0.5 h, and then 100 μL HCl (1 mol/L) was added for neutralization. Subsequently, 3 mL methanol was added to dissolve the cracked DAS and OLA, which were mixed evenly and centrifuged (5000 rpm, 10 min).…”
Purpose
This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application.
Methods
In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo.
Results
In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs.
Conclusion
DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.
“…As shown in Figure 6A and B , the accumulation of DAS and OLA in the HDO-NPs group was higher than that in the free DAS + OLA group at each time point, owing to the introduction of hyaluronic acid, which could be better taken up by tumor cells and increase drug endocytosis. 38 Meanwhile, the drug accumulations in the HA blocking group were lower than that in the HDO-NPs group, which also reflected the above conjecture, further showing that the targeting of HA can enhance the accumulation of drugs in cells. Figure 6 The accumulation of ( A ) DAS and ( B ) OLA in MDA-MB-231 cells incubated with DAS + OLA, HA + HDO-NPs and HDO-NPs for different times.…”
Section: Resultssupporting
confidence: 52%
“…HDO-NPs were hydrolyzed by strong alkaline hydrolysis to determine the drug loading and encapsulation efficiency of DAS and OLA. 37 , 38 In short, 4 mg HDO-NPs were dissolved in 1 mL deionized water, 100 μL NaOH (1 mol/L) was added for 0.5 h, and then 100 μL HCl (1 mol/L) was added for neutralization. Subsequently, 3 mL methanol was added to dissolve the cracked DAS and OLA, which were mixed evenly and centrifuged (5000 rpm, 10 min).…”
Purpose
This study emphasized that dasatinib (DAS) and olaparib (OLA) have synergistic effects on triple negative breast cancer, by inducing DNA damage and inhibiting DNA damage repair. However, poor water solubility, short half-life of drugs, and low drug concentration in tumor tissue limit the clinical application.
Methods
In this research, acid-sensitive ester bonds were used to connect hydrophobic DAS and hydrophilic hyaluronic acid (HA) to form the amphiphilic polymer prodrug HA-DAS, and then OLA was added as the core, the HA-DAS was used as the carrier to form nanomicelles (HDO-NPs) in aqueous. The characterization and drug release of HDO-NPs were studied, and the cytotoxicity, targeting effect, and intracellular transport behavior of HDO-NPs were evaluated in MDA-MB-231. In addition, the pharmacokinetic and therapeutic effect of HDO-NPs were further verified in vivo.
Results
In vitro characterizations showed that HDO-NPs were spherical with uniform particle size, good stability and anti-dilution ability, and displayed favorable pH-responsive drug release behavior. In addition, the cell experiments showed that HDO-NPs could be effectively taken up by binding to the overexpressed CD44 proteins of MDA-MB-231 cells, resulting in increased intracellular drug concentration. In vivo experiments showed that HDO-NPs can effectively target tumor tissues, have excellent therapeutic effects on tumor, significantly prolong the circulation time of drugs in vivo, and effectively improved the bioavailability of drugs.
Conclusion
DAS and OLA were designed into micelles, the efficacy of HDO-NPs was higher than that of free drugs. Therefore, HDO-NPs have good application prospects in the treatment of triple negative breast cancer.
“…As shown in Figure A, B, the fluorescence intensity of ICG-Osi increased in a dose- and pH-dependent manner. The strongest fluorescence intensity was detected at a pH level of 5.5, similar to that of the tumor microenvironment . These results suggested that ICG-Osi could therefore be used for in vivo tumor tracking.…”
In nonsmall cell lung cancers (NSCLC), near-infrared
(NIR) fluorescence
imaging using indocyanine green (ICG) has proven to be an efficient
approach for locating pulmonary nodules and pulmonary sentinel lymph
nodes. However, due to a lack of tumor selectivity, ICG’s use
as a photosensitizer for photothermal therapy (PTT) and photodynamic
therapy (PDT) is restricted. In the current study, we aimed to develop
a type of high-performance NIR nanoparticle formulated with ICG to
enhance its targeted efficacy and tumor specificity on NSCLC. An ICG-osimertinib
nanoparticle (ICG-Osi) was self-assembled through π–π stacking, with a size of 276 nm and a surface charge of −7.4
mV. The NIR visibility and epidermal growth factor receptor (EGFR)
targetability of the ICG-Osi was confirmed by its binding efficiency
to EGFR-expressing NSCLC cells in vitro and in vivo, regardless of EGFR mutation status. The targeted
effect was further confirmed in mouse xenograft models and showed
an extended tumor retention time (>96 h). We demonstrated a significantly
enhanced hyperthermia effect and a retained reactive oxygen species
(ROS) generating ability of ICG-Osi, resulting in a 2-fold higher
cell death rate than ICG alone. The ICG-Osi down-regulated GPX4 and
p62 expression while up-regulating caspase-3 and beclin1 expression
in NSCLC cells, indicating a complex network of cell death-related
proteins. Considering the merits of simple assembly, EGFR binding
efficacy, improved hyperthermia effect, and efficient cancer cell
suppression, the ICG-Osi exhibits great potential for clinical application
in EGFR-expressing NSCLC therapy.
“…The natural polymers used for gene-based therapy include chitosan, atelocollagen, folate (FA), HA, and gelatin, and are biocompatible, biodegradable, and generally nontoxic, even at high concentrations. Chitosan has been successfully used in gene delivery systems [155][156][157]. Novel chitosan nanoparticles were developed to deliver functional miRNA mimics to macrophages through regulating ABCA1 expression and cholesterol efflux to target atherosclerotic lesions [158].…”
Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials.
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