Cyclosporine-A (CsA) is generally used as an immunosuppressant and is also prescribed for some ophthalmic applications such as vernal keratoconjunctivitis and dry eye. However, it is limited clinically due to its low aqueous solubility and ocular bioavailability.In this work, lyophilized methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) polymer micelles were prepared for ophthalmic formulations as a promising nanocarrier for hydrophobic drugs like CsA. A mPEG-PLA diblock polymer was synthesized by ring opening polymerization and CsA was loaded into mPEG-PLA micelles by a simple film dispersion method. A uniform design of experiments was utilized to optimize the final formulation. The obtained formulation was characterized for diameter (57.0±3.2 nm), entrapment efficiency % (98.51±1.4), and in vitro release. Moreover, incorporating the stabilizer mPEG2000 could increase the in vitro stability of the lyophilized CsA-loaded mPEG-PLA micelles.Results showed a sustained release of CsA from the micelles. Drug concentration and time-dependent cytotoxicity of human corneal epithelial-2 cells was observed. Additionally, the transcorneal mechanism of mPEG-PLA micelles was studied and the results showed that the mPEG-PLA micelles mainly absorbed by a paracellular pathway via corneal epithelial cells.Taken together, the results proved that this mPEG-PLA diblock polymer can be potentially used as a nanoscopic carrier to deliver hydrophobic drugs in a controlled manner to the ocular region and, thus, deserves further attention.
Protein corona (PC) has been identified to impede the transportation of intravenously injected nanoparticles (NPs) from blood circulation to their targeted sites. However, how intestinal PC (IPC) affects the delivery of orally administered NPs are still needed to be elucidated. Here, we found that IPC exerted "positive effect" or "negative effect" depending on different pathological conditions in the gastrointestinal tract. We prepared polystyrene nanoparticles (PS) adsorbed with different IPC derived from the intestinal tract of healthy, diabetic, and colitis rats (H-IPC@PS, D-IPC@PS, C-IPC@PS). Proteomics analysis revealed that, compared with healthy IPC, the two disease-specific IPC consisted of a higher proportion of proteins that were closely correlated with transepithelial transport across the intestine. Consequently, both D-IPC@PS and C-IPC@PS mainly exploited the recycling endosome and ER-Golgi mediated secretory routes for intracellular trafficking, which increased the transcytosis from the epithelium. Together, disease-specific IPC endowed NPs with higher intestinal absorption. D-IPC@PS posed "positive effect" on intestinal absorption into blood circulation for diabetic therapy. Conversely, C-IPC@PS had "negative effect" on colitis treatment because of unfavorable absorption in the intestine before arriving colon. These results imply that different or even opposite strategies to modulate the disease-specific IPC need to be adopted for oral nanomedicine in the treatment of variable diseases.
Abstract Oral delivery is the most widely used modality for drug administration, but its efficiency is hampered by the limited drug absorption in the gastrointestinal tract. To address this issue, neonatal‐Fc‐receptor‐targeted liposome (Fc domain‐binding peptide (FcBP)‐Lip) is designed in this study. It is discovered that FcBP modification, by adapting to longitudinal pH gradience of the intestine, increases the unidirectional transport of liposomes from the apical to the basolateral side of the intestinal epithelium. In addition, FcBP‐Lip circumvents the lysosomal sequestration and engages the endoplamic reticulum (ER)–Golgi secretion pathway, together contributing to another mechanism that enhances epithelium transcytosis. Moreover, it is discovered that FcBP‐Lip is subject to paracellular and lymphatic transportations by activating specific intracellular kinases and forming chylomicron, respectively. Owing to the vigorous involvement of the miscellaneous transepithelial transport pathways, oral absorption of FcBP‐Lip in vivo is significantly increased. Finally, the insulin that is encapsulated into FcBP‐Lip elicits a stronger hypoglycemic effect than the native form. Notably, insulin‐loaded FcBP‐Lip efficiently elevates hepatic insulin accumulation, insulin receptor level, and glycogen production, leading to blood glucose homeostasis in diabetic rats.
College administrative management level is one of important standards to judge the overall level of universities and colleges.Under the new circumstance of higher educational reform in China, college administrative management plays a very important role in higher educational reform.Therefore, improving the administrative management capability and work efficiency in Chinese universities and colleges will play significant function in promoting university reform in china.This article discusses the important value of college administrative management, analyzed existing problems, and elaborated some specific reform measures to solve these problems.
Enhanced Hepatocellular Carcinoma Therapy First-line hepatocellular carcinoma treatment is sorafenib, but effectiveness of sorafenib is relatively low due to a lack of tumor-targeted accumulation and a lack of therapeutic efficacy. In article number 2301149, Yuan Huang and co-workers design orally administered butyrate-modified nanoparticles, which could strongly bind to monocarboxylate transporter 1 (MCT-1) receptors and efficiently penetrate the intestinal epithilium to deliver ferroptosis inducers for the treatment of liver tumors by pronounced ferroptosis damage.
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-β-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.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)