Mucus-Penetrating Silk Fibroin-Based Nanotherapeutics for Efficient Treatment of Ulcerative Colitis.

Oral nanoparticles have been considered a prospective drug delivery carrier against ulcerative colitis (UC). To enhance the mucus-penetrating capacity and aqueous solubility, and strengthen the anti-inflammatory effect of resveratrol (RSV), we fabricated RSV-loaded silk fibroin-based nanoparticles with the functionalization of Pluronic F127 (PF-127). The obtained PF-127-functionalized RSV-loaded NPs had an average particle size around 170 nm, a narrow size distribution (polydispersity index < 0.2), and negative zeta potential (−20.5 mV). Our results indicated that the introduction of PF-127 strengthened the mucus-penetrating property of NPs. In vitro studies suggested that NPs with PF-127 enhanced the suppression of the secretion of proinflammatory cytokine TNF-α and reactive oxygen species (ROS) from RAW 264.7 macrophages under lipopolysaccharide stimulation in comparison with other counterparts. According to the evaluation of macro symptoms and main inflammatory cytokines, we further report preferable therapeutic outcomes achieved by PF-127 functionalized-NP-treated dextran sulphate sodium (DSS) groups in the colitis model compared with blank silk fibroin NPs and RSV-loaded NPs without the functionalization of PF-127. Taken together, this work suggests that the fabricated PF-127 NPs via the oral route are promising and useful RSV-loaded nanocarriers for UC treatment.

'Green' nanotherapeutics from tea leaves for orally targeted prevention and alleviation of colon diseases.

Although synthesized nanotherapeutics (NTs) are attractive for the oral treatment of colon diseases, their clinical translations are constrained by the unsatisfactory therapeutic outcomes, potential adverse effects, and high cost of mass production. Here, we report the development of tea leaf-derived natural NTs with desirable particle sizes (140.0 nm) and negative surface charge (-14.6 mV). These natural exosome-like NTs were found to contain large amounts of lipids, some functional proteins, and many bioactive small molecules. Specifically, galactose groups on the surface of NTs could mediate their specific internalization by macrophages via galactose receptor-mediated endocytosis. Moreover, these NTs were able to reduce the production of reactive oxygen species, inhibit the expression of pro-inflammatory cytokines, and increase the amount of anti-inflammatory IL-10 secreted by macrophages. Orally administered NTs could efficiently inhibit the inflammatory bowel responses, restore disrupted colonic barriers and enhance the diversity and overall abundance of gut microbiota, thereby preventing or alleviating inflammatory bowel disease and colitis-associated colon cancer. The present study brings new insights to the facile application of a versatile and robust natural nanoplatform for the prevention and treatment of colon diseases.

Oral delivery of natural active small molecules by polymeric nanoparticles for the treatment of inflammatory bowel diseases.

The incidence of inflammatory bowel disease (IBD) is rapidly rising throughout the world. Although tremendous efforts have been made, limited therapeutics are available for IBD management. Natural active small molecules (NASMs), which are a gift of nature to humanity, have been widely used in the prevention and alleviation of IBD; they have numerous advantageous features, including excellent biocompatibility, pharmacological activity, and mass production potential. Oral route is the most common and acceptable approach for drug administration, but the clinical application of NASMs in IBD treatment via oral route has been seriously restricted by their inherent limitations such as high hydrophobicity, instability, and poor bioavailability. With the development of nanotechnology, polymeric nanoparticles (NPs) have provided a promising platform that can efficiently encapsulate versatile NASMs, overcome multiple drug delivery barriers, and orally deliver the loaded NASMs to targeted tissues or cells while enhancing their stability and bioavailability. Thus, NPs can enhance the preventive and therapeutic effects of NASMs against IBD. Herein, we summarize the recent knowledge about polymeric matrix-based carriers, targeting ligands for drug delivery, and NASMs. We also discuss the current challenges and future developmental directions.

Quadruple-responsive nanoparticle-mediated targeted combination chemotherapy for metastatic breast cancer.

The synergism of combination chemotherapy can only be achieved under specific drug ratios. Herein, hyaluronic acid (HA)-functionalized regenerated silk fibroin-based nanoparticles (NPs) were used to concurrently deliver curcumin (CUR) and 5-fluorouracil (5-FU) at various weight ratios (3.3 : 1, 1.6 : 1, 1.1 : 1, 1 : 1, and 1 : 1.2) to breast tumor cells. The generated HA-CUR/5-FU-NPs were found to have desirable particle sizes (around 200 nm), narrow size distributions, and negative zeta potentials (about -26.0 mV). Interestingly, these NPs showed accelerated drug release rates when they were exposed to buffers that mimicked the multi-hallmarks in the tumor microenvironment (pH/hydrogen peroxide/glutathione/hyaluronidase). The surface functionalization of NPs with HA endowed them with in vitro and in vivo breast tumor-targeting properties. Furthermore, we found that the co-loading of CUR and 5-FU in HA-functionalized NPs exhibited obvious synergistic anti-cancer, pro-apoptotic, and anti-migration effects, and the strongest synergism was found at the CUR/5-FU weight ratio of 1 : 1.2. Most importantly, mice experiments revealed that HA-CUR/5-FU-NPs (1 : 1.2) showed a superior anti-cancer activity against metastatic breast cancer compared to the single drug-loaded NPs and non-functionalized CUR/5-FU-NPs (1 : 1.2). Collectively, these results demonstrate that HA-CUR/5-FU-NPs (1 : 1.2) can be exploited as a robust nanococktail for the treatment of breast cancer and its lung metastasis.

Pluronic F127-Modified Electrospun Fibrous Meshes for Synergistic Combination Chemotherapy of Colon Cancer.

Colon cancer ranks as the third most common malignancy in the world. Combination chemotherapy, resorting to electrospun fibrous technology, has been considered as a promising strategy to exert synergistic effects in colon cancer treatment. Herein, we manufactured various pluronic F127 (PF127)-modified electrospun fibrous meshes with different weight ratios of camptothecin (CPT) and curcumin (CUR). The fluorescence characterization of the obtained PF127-CPT-meshes, PF127-CUR-meshes, and PF127-CPT/CUR-meshes (2:1) showed that CPT and CUR were evenly distributed within individual fibers of these meshes. Drug release experiments revealed that both types of drugs could be released from fibrous meshes simultaneously and sustainably. Importantly, these meshes exhibited strong in vitro anti-colon cancer activities, compared with the control meshes without drugs. Moreover, the combination index values of the PF127-CPT/CUR-meshes (CPT/CUR weight ratio = 5:1, 3:1, or 2:1) were <0.5 after incubation for respective 24 and 36 h, indicating the synergistic anti-colon cancer effects of CPT and CUR in fibrous meshes. Collectively, these results demonstrate that PF127-CPT/CUR-meshes can be developed as an efficient implantable system for effective synergistic treatment of colon cancer.

Injectable, Thixotropic, and Multiresponsive Silk Fibroin Hydrogel for Localized and Synergistic Tumor Therapy.

Combinational cancer therapy offers a promising strategy to overcome the limitations of single-drug treatment, including limited therapeutic efficacy, serious side effects, and low survival rate. Injectable silk fibroin (SF) hydrogel has emerged as an effective platform for localized treatment. Herein, hydrophilic SF (HSF) was extracted from regenerated SF and self-assembled into hydrogel within 2-6 h. The obtained HSF hydrogel showed obvious viscoelasticity, thixotropic behavior, and self-healing performance. Interestingly, this hydrogel also exhibited excellent stimuli-responsive drug release profiles when triggered by multiple factors (acidity, reactive oxygen species, glutathione, hyperthermia, and near-infrared (NIR)), suggesting that it could achieve spatially and temporally on-demand drug release in response to tumor microenvironment and extra-tumor NIR irradiation. Importantly, intratumoral injection of doxorubicin (DOX)/Cy7-loaded HSF-based hydrogel (DOX/Cy7-hydrogel) plus NIR irradiation exerted the best antitumor effect among all the treatment groups, revealing the strong synergistic effects of chemo/photothermal/photodynamic therapy. It is worth noting that this DOX/Cy7-hydrogel could almost eliminate the entire tumor masses, significantly prolonging the survival time of tumor-bearing mice over 60 days without detectable adverse effects. Collectively, our findings suggest that this injectable DOX/Cy7-hydrogel with thixotropic and multistimuli responsive properties could be developed as a promising platform for localized and synergistic treatment of cancer.

Chondroitin sulfate-functionalized polymeric nanoparticles for colon cancer-targeted chemotherapy.

Targeted delivery of chemotherapeutic drugs to tumors is a major challenge in colon cancer chemotherapy. To overcome this bottleneck, we loaded camptothecin (CPT) into polymeric nanoparticles (NPs), and further functionalized their surface with chondroitin sulfate (CS). The resulting CS-CPT-NPs had a desirable hydrodynamic diameter (289 nm), narrow particle size distribution (polydispersity index = 0.192) and neutral surface charge. Furthermore, in vitro experiments revealed that the surface functionalization of CS endowed NPs with the capacity of colon cancer-targeted drug delivery, and significantly improved the anti-colon cancer activities and pro-apoptosis effects against colon cancer cells. Strikingly, treatment of colon tumor-bearing mice with different NPs clearly indicated that CS-CPT-NPs showed much better therapeutic outcomes than non-targeted NPs and no systemic toxicity. Taken together, these results demonstrated the promising potential of CS-CPT-NP as an effective drug delivery system for colon cancer-targeted chemotherapy.