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► A silane-free route was developed to graft PEG onto the external surface of MSNs. ► The combined goals of drug delivery and liver cancer cell targeting were achieved. ► The loaded ...DOX demonstrated a pH-dependent release feature. ► DOX was more effectively delivered to targeted cells and induced their apoptosis.
A layer of PEG (poly(ethylene glycol))-galactose was successfully grafted onto the external surface of mesoporous silica nanoparticles (MSNs) via a new silane-free approach, while the internal surface of MSNs was preserved for the encapsulation of the widely used anti-cancer drug of doxorubicin (DOX). The nanosized morphology and ordered structure of the synthesized drug delivery vehicles were verified by XRD and TEM observations. The successful grafting of PEG layer and peripherally exposed galactose ligands on the external surface of MSNs (abbreviated as MSNs-P/G) was confirmed by FT-IR and solid 13C NMR. The high-density PEG layer effectively reduced the human serum protein (HSP) adsorbance to the surface of MSNs. The maximum DOX loading amount reached as high as 900mg/g and the loaded drug released in a pH-dependent way. Both confocal laser scanning microscopy (CLSM) observation and flow cytometry measurements supported the facts that cellular uptake of MSNs-P/G was significantly higher than that of the pristine MSNs benefitting from the galactose-receptor-mediated endocytosis process. This was consistent with the higher cytotoxicity observed with the DOX@MSNs-P/G against the HepG2 cell line by MTT measurements.
Background: Traumatic brain injury (TBI) is associated with a range of neural changes. A comprehensive understanding of the injury-induced lysine acetyltransferase 6A (KAT6A) response, particularly ...the temporal profile of biochemical alterations, is crucial to design effective therapeutic interventions.Methods: Experiments were performed in male Sprague-Dawley rats. The influence of post-traumatic hypothermia (32°C) or hyperthermia (39°C) on the temporal and regional expression profiles of KAT6A was assessed after moderate or severe TBI. qPCR and western blotting were used to determine the expression of KAT6A in different groups.Results: In the ipsilateral and contralateral hemispheres, significantly lower protein and mRNA expression of KAT6A was found after TBI than sham injury. Moreover, two expression minima of KAT6A were observed in the cortex and hippocampus of the ipsilateral hemisphere. A decrease in injury severity was associated with lower levels of KAT6A mRNA at 12 h and protein at 24 h, but KAT6A mRNA at 48 h and protein at 72 h had alterations. Compared with normothermia and hyperthermia, post-traumatic hypothermia intensified the decrease in KAT6A at both the mRNA and protein levels. In contrast, hyperthermia, as compared with normothermia, did not significantly affect the levels of KAT6A mRNA at 12 h and protein at 24 h, but triggered a significant increase in levels of KAT6A mRNA at 24 h and protein at 72 h. Furthermore, an overall upregulation of KAT6A after TBI was associated with greater injury severity in a time-dependent manner.Conclusions: Post-traumatic hypothermia plays a key role in the regulation of KAT6A expression and thus may at least partially explain the phenotype of post-traumatic temperature in secondary injury after TBI.
Allergic rhinitis (AR) is a prevalent immune-related allergic disease, and corticosteroid nasal sprays serve as the primary treatment for this patient population. However, their short duration of ...efficacy and frequent administration pose challenges, leading to drug wastage and potential adverse effects. To overcome these limitations, we devised a novel approach to formulate DEX-Gel by incorporating dexamethasone (DEX) into a blend of Pluronic F127, stearic acid (SA), and polyethylene glycol 400 (PEG400) to achieve sustained-release treatment for AR. Following endoscopic injection into the nasal mucosa of AR rats, DEX-Gel exhibited sustained release over a 14-day period. In vivo trials employing various assays, such as flow cytometry (FC), demonstrated that DEX-Gel not only effectively managed allergic symptoms but also significantly downregulated helper T-cells (T.sub.H) 2 and T.sub.H2-type inflammatory cytokines (e.g., interleukins 4, 5, and 13). Additionally, the T.sub.H1/T.sub.H2 cell ratio was increased. This innovative long-acting anti-inflammatory sustained-release therapy addresses the T.sub.H1/T.sub.H2 immune imbalance, offering a promising and valuable approach for the treatment of AR and other inflammatory nasal diseases.
Orodispersible films (ODFs) as a relatively novel delivery platform have increasingly attracted enormous attention owing to their various advantages compared to conventional oral dosage forms, ...including fast disintegration, ease of administration without consumption of water, and rapid absorption of incorporated drug, high patient compliance for pediatrics, geriatrics and patients with swallowing difficulties. This review aims to summarize the developments and possibilities that ODFs as the potential carrier for chemical drugs, vaccine, probiotics, and herbal extracts. Especially, with the outbreak of coronavirus disease 2019 (COVID‐19), the advantages of ODFs related to ease of transporation and distribution without cold‐chain as well as low‐cost manufacturing make ODFs a promising carrier for vaccines against COVID‐19. Subsequently, the current therapeutic applications of ODFs delivered either locally or systemically for potential patients suffering from various diseases are discussed, including oral inflammation, cardiovascular diseases, pain disorders, nausea and vomiting, mood or mental disorders, erectile dysfunction and pulmonary diseases. Finally, this review provides overview of the novel inkjet printing and three‐dimensional printing techniques, and the possibility of extemporaneous preparation for ODFs in hospital pharmacies via printing techniques are discussed as well.
The current therapeutic applications of orodispersible films (ODFs) are delivered either locally or systemically for potential patients suffering from various diseases, including oral inflammation, cardiovascular diseases, pain disorders, nausea and vomiting, mood or mental disorders, erectile dysfunction and pulmonary diseases
Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast ...cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 + or - 1.002 nm and - 10.6 + or - 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.
CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of ...therapeutic agents remains largely incomplete. Here, patients with liver cancer co‐expressing CD47 and CDC7 (cell division cycle 7, a negative senescence‐related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual‐targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy‐resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.
The sequential release of a senescence inducer (CDC7 inhibitor) and a CD47 inhibitor from the dual‐targeting nanosystem in situ induced senescence and antitumor immune responses to aganist liver cancer and overcome chemoresistance.
Copolymers were synthesized by ring opening polymerization of
l- or
d-lactide in the presence of dihydroxyl PEG with molar mass of 6000, 12,000 and 20,000, using zinc lactate as catalyst. ...Bioresorbable hydrogels were obtained by mixing PLLA–PEG–PLLA and PDLA–PEG–PDLA aqueous solutions due to stereocomplexation between PLLA and PDLA chains. Rheological measurements show that the hydrogels present typical viscoelastic behaviors, although degradation could occur during the gelation process. Thymopentin was taken as a model drug to evaluate the potential of PLA–PEG–PLA hydrogels as carrier of hydrophilic drugs. Various parameters such as copolymer concentration, drug load, copolymer composition and the difference between sol and gel were considered. The release profiles are characterized by an initial burst followed by slower release. Higher copolymer concentration leads to slower release rate and less burst effect due to more compact structure which disfavors drug diffusion. Similarly, higher molar mass of the copolymers disfavors the release of TP5, and hydrogels composed of both PLLA/PEG and PDLA/PEG present slower release rates than single copolymer solutions. In contrast, drug load exhibits little influence on the release profiles due to the high water solubility of TP5. In all cases, nearly 80% of TP5 is released. In vivo studies proved the potential of TP5 containing hydrogels, especially those with a concentration of 25%. Both the CD4
+/CD8
+ ratio and the morphology of thymus indicate the immunization efficacy of the TP5 release systems based on PLA/PEG hydrogels.
The flow fields generated by the acoustic behavior of microbubbles can significantly increase cell permeability. This facilitates the cellular uptake of external molecules in a process known as ...ultrasound-mediated drug delivery. To promote its clinical translation, this study investigated the relationships among the ultrasound parameters, acoustic behavior of microbubbles, flow fields, and delivery results. SonoVue microbubbles were activated by 1 MHz pulsed ultrasound with 100 Hz pulse repetition frequency, 1:5 duty cycle, and 0.20/0.35/0.70 MPa peak rarefactional pressure. Micro-particle image velocimetry was used to detect the microbubble behavior and the resulting flow fields. Then HeLa human cervical cancer cells were treated with the same conditions for 2, 4, 10, 30, and 60 s, respectively. Fluorescein isothiocyanate and propidium iodide were used to quantitate the rates of sonoporated cells with a flow cytometer. The results indicate that (1) microbubbles exhibited different behavior in ultrasound fields of different peak rarefactional pressures. At peak rarefactional pressures of 0.20 and 0.35 MPa, the dispersed microbubbles clumped together into clusters, and the clusters showed no apparent movement. At a peak rarefactional pressure of 0.70 MPa, the microbubbles were partially broken, and the remainders underwent clustering and coalescence to form bubble clusters that exhibited translational oscillation. (2) The flow fields were unsteady before the unification of the microbubbles. After that, the flow fields showed a clear pattern. (3)The delivery efficiency improved with the shear stress of the flow fields increased. Before the formation of the microbubble/bubble cluster, the maximum shear stresses of the 0.20, 0.35, and 0.70 MPa groups were 56.0, 87.5 and 406.4 mPa, respectively, and the rates of the reversibly sonoporated cells were 2.4% ± 0.4%, 5.5% ± 1.3%, and 16.6% ± 0.2%. After the cluster formation, the maximum shear stresses of the three groups were 9.1, 8.7, and 71.7 mPa, respectively. The former two could not mediate sonoporation, whereas the last one could. These findings demonstrate the critical role of flow fields in ultrasound-mediated drug delivery and contribute to its clinical applications.
The binding of amyloid precursor protein (APP) expressed on tumor cells to death receptor 6 (DR6) could initiate the necroptosis pathway, which leads to necroptotic cell death of vascular endothelial ...cells (ECs) and results in tumor cells (TCs) extravasation and metastasis. This study reports the first inhibitor of DR6/APP interaction as a novel class of anti‐hematogenous metastatic agent. By rationally utilizing three combined strategies including selection based on phage display library, d‐retro‐inverso modification, and multiple conjugation of screened peptidomimetic with 4‐arm PEG, the polymer–peptidomimetic conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG5k) is obtained as the most promising agent with the strongest binding potency (KD = 51.12 × 10−9 m) and excellent pharmacokinetic properties. Importantly, PEG‐tAHP‐DRI provides efficient protection against TC‐induced ECs necroptosis both in vitro and in vivo. Moreover, this ligand exhibits prominent anti‐hematogenous metastatic activity in serval different metastatic mouse models (B16F10, 4T1, CT26, and spontaneous lung metastasis of 4T1 orthotopic tumor model) and displays no apparent detrimental effects in preliminary safety evaluation. Collectively, this study demonstrates the feasibility of exploiting DR6/APP interaction to regulate hematogenous tumor cells transendothelial migration and provides PEG‐tAHP‐DRI as a novel and promising inhibitor of DR6/APP interaction for developments of anti‐hematogenous metastatic therapies.
Binding of amyloid precursor protein (APP) and death receptor 6 (DR6) is shown to initiate the necroptosis pathway and lead to tumor cells metastasis. The combined strategies of selection based on phage display library, d‐retro‐inverso modification, and multiple conjugation result in the development of conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG5k) that blocks APP‐DR6 interactions and shows promising anti‐hematogenous metastatic activity both in vitro and in vivo.
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