Inhibition of growth and lung metastasis of breast cancer by tumor-homing triple-bioresponsive nanotherapeutics.

Lung metastasis of breast cancer is a leading cause of cancer-related death in women. Herein, we attempted to simultaneously inhibit the growth and lung metastasis of breast cancer by delivering quercetin (QU) using LyP-1-functionalized regenerated silk fibroin-based nanoparticles (NPs). The generated LyP-1-QU-NPs had a desirable diameter (203.2 nm) and a negatively charged surface (-12.7 mV). Interestingly, these NPs exhibited intrinsic responsibilities when triggered by various stimulating factors in the tumor microenvironment (acidic pH, reactive oxygen species, and glutathione). In vitro experiments revealed that the introduction of LyP-1 to the NP surface could significantly increase their cellular uptake efficiencies by 4 T1 cells, and facilitate their accumulation in mitochondria. Moreover, LyP-1-QU-NPs showed the strongest mitochondrial damage effect among all the treatment groups. We also found that LyP-1-QU-NPs not only exhibited excellent pro-apoptotic activities but also presented strong inhibitory effects on cell mobility (migration and invasion) through anti-glycolysis and pro-autophagy. Mice experiments confirmed that LyP-1-QU-NPs could efficiently inhibit the in situ growth of breast tumors and further restrict their lung metastasis. Collectively, our results demonstrate that LyP-1-QU-NPs, which integrates the functions of tumor cell targeting, mitochondria targeting, bioresponsive drug release, pro-apoptosis, and anti-mobility, can be developed as a promising nanotherapeutic for the effective treatment of breast cancer and its lung metastasis.

Internalization of Garlic-Derived Nanovesicles on Liver Cells is Triggered by Interaction With CD98.

The mechanism of how plant-derived nanovesicles are uptaken by cells remains unknown. In this study, the garlic-derived nanovesicles (GDVs) were isolated and digested with trypsin to remove all surface proteins. Digested GDVs showed less uptake compared to undigested GDVs, confirming that the surface proteins played a role in the endocytosis. On the cell side (HepG2), interestingly, blocking the CD98 receptors significantly reduced the uptake of GDVs. During the cellular internalization of GDVs, we observed that some surface proteins of GDVs were co-localized with CD98. A total lysate of the GDV surface showed a high presence of a mannose-specific binding protein, II lectin. Blocking GDV II lectin (using mannose preincubation) highly reduced the GDV internalization, which supports that direct interaction between II lectin and CD98 plays an important role in internalization. The GDVs also exhibited in vitro anti-inflammatory effect by downregulating proinflammatory factors on the HepG2 cells. This work contributes to understanding a part of the GDV internalization process and the cellular anti-inflammatory effects of garlic.

Machine-Driven Chemoenzymatic Synthesis of Glycopeptide.

Historically, researchers have put considerable effort into developing automation systems to prepare natural biopolymers such as peptides and oligonucleotides. The availability of such mature systems has significantly advanced the development of natural science. Over the past twenty years, breakthroughs in automated synthesis of oligosaccharides have also been achieved. A machine-driven platform for glycopeptide synthesis by a reconstructed peptide synthesizer is described. The designed platform is based on the use of an amine-functionalized silica resin to facilitate the chemical synthesis of peptides in organic solvent as well as the enzymatic synthesis of glycan epitopes in the aqueous phase in a single reaction vessel. Both syntheses were performed by a peptide synthesizer in a semiautomated manner.

Orally delivered targeted nanotherapeutics for the treatment of colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC), the third-most common malignancy, has high morbidity and mortality. Oral nanotherapeutics have emerged as a promising strategy to improve the therapeutic outcomes and alleviate the adverse effects of drugs in CRC treatment. AREAS COVERED: In this review, we introduce the beneficial features of oral drug administration for CRC therapy, and further address the three basic elements of nanotherapeutics, namely, therapeutic agents, carrier materials, and targeting ligands. In addition, we also discuss the potentials of the new emerging technologies (e.g., immunotherapy, gene editing and microbiota manipulation) in the treatment of CRC. EXPERT OPINION: Orally delivered targeted nanotherapeutics represent a promising strategy toward the efficient treatment of CRC. Although the current oral nanotherapeutics exert better therapeutic outcomes than the traditional drug formulations, their application has been restricted by drug resistance, tumor metastasis, and biosafety. Therefore, it is necessary to exploit new nanotherapeutics in the aspects of their three basic elements, and combine the new emerging technologies to those nanotherapeutics for CRC treatment.

Role of CD98 in liver disease.

CD98 is a multifunctional glycoprotein that is involved in various biological processes such as amino acid transport, cell adhesion, diffusion, adhesion, and proliferation. The role of CD98 in liver disease has not thoroughly been examined and is limited reports in the literature. Among these reports, direct association for CD98 in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) have been reported. Our lab has reported that targeting CD98 in high fat diet mice reduced steatosis and inflammation in NAFLD. Other reports associate CD98 in HCC due in part to the role of CD98 in activating integrin signaling. Herein, we present CD98 staining on liver biopsies from NAFLD, chronic active hepatitis, cirrhosis, and 3 stages of HCC to demonstrate the upregulation of CD98 expression throughout liver disease progression. In addition, we analyze current literature to elucidate roles and potential roles of CD98 with each stage of liver disease.

Lycium barbarum lipid-based edible nanoparticles protect against experimental colitis.

Edible plant-derived nanoparticles (NPs) have attracted increasing attention in the treatment of ulcerative colitis (UC). Lycium barbarum (LB), a popular functional fruit, possesses various biological functions. Here, fat-soluble contents were extracted from LB and further processed into LB lipid-derived NPs (LBLNs). The resultant NPs had an average hydrodynamic diameter around 189.2 nm, narrow size distribution (polydispersity index = 0.2), and negative surface charge (-34.9 mV). Moreover, they could be efficiently taken up by UC therapy-related target cells (macrophages), and over 69.0 % of macrophages internalized LBLNs after 4 h co-incubation. We further found from the in vitro results that LBLNs had strong capacities to inhibit the secretion of the main pro-inflammatory cytokines (TNF-α and IL-12) and up-regulate the expression of the typical anti-inflammatory factor (IL-10). Finally, mice experiments confirmed that LBLNs after oral administration could specifically accumulate into inflamed colon tissues, and further attenuate UC-relevant symptoms (e.g., bodyweight loss, colon shortening, increase of spleen weight, and histopathological appearance, as well as ulceration). Collectively, this study demonstrates the excellent therapeutic outcomes of LBLNs against UC and provides a promising edible nanotherapeutic for UC treatment.

Oral administration of chondroitin sulfate-functionalized nanoparticles for colonic macrophage-targeted drug delivery.

Orally targeted delivery of anti-inflammatory drugs to macrophages has attracted great attention for minimizing the symptoms of ulcerative colitis (UC). In this investigation, we encapsulated curcumin (CUR) into polymeric nanoparticles (NPs), and conjugated chondroitin sulfate (CS) to their surfaces. The resulting CS-NPs had an average diameter of 281 nm, monodisperse size distribution and negatively charged surface. Cell experiments indicated that these NPs showed excellent biocompatibility, and yielded significantly higher cell internalization efficiency in Raw 264.7 macrophages than their counterparts (carboxymethyl cellulose-functionalized CUR-encapsulated NPs, CUL-NPs). Moreover, CS-NPs exhibited a dramatically stronger capacity to inhibit the secretion of the major pro-inflammatory cytokines from lipopolysaccharide-stimulated macrophages compared with CUL-NPs. In vivo experiments revealed that oral administration of chitosan/alginate hydrogel embedding CS-NPs achieved better therapeutic outcomes against UC comparied with CUL-NPs. Collectively, our results demonstrated that CS-NP-embedded hydrogel held a great promise to be developed as a macrophage-targeted drug delivery system for UC treatment.

Facile Fabrication of Oxidation-Responsive Polymeric Nanoparticles for Effective Anticancer Drug Delivery.

Reactive oxygen species (ROS) are highly overproduced in cancerous tissues, and thus oxidation-responsive nanoparticles (NPs) have emerged as a promising drug carrier for cancer-targeted drug delivery. In this study, we successfully synthesized poly(vanillyl alcohol- co-oxalate) (PVAX) polymer with an excellent ROS-responsive capacity. A well-established emulsion-solvent evaporation method was used to fabricate PVAX-based curcumin (CUR)-loaded NPs (PVAX-NPs) and their counterparts (poly(lactic- co-glycolic acid)-based CUR-loaded NPs, PLGA-NPs). It was found that these NPs had a hydrodynamic particle size of approximately 245 nm, narrow size distribution (polydispersity index less than 0.1), negative zeta potential (around -18 mV), smooth surface appearance, and high drug encapsulation efficiency. Moreover, we found that the CUR release rate of PVAX-NPs was greatly increased in the presence of a hydrogen peroxide-rich environment due to the cleavage of polyoxalate ester bonds in PVAX polymer, resulting in the evenly distribution of CUR within the whole cancer cells. More importantly, PVAX-NPs exhibited much stronger anticancer activities and pro-apoptotic capacities than PLGA-NPs both in vitro and in vivo. These results clearly demonstrate that these ROS-responsive PVAX-NPs can be exploited as a robust anticancer drug delivery platform in chemotherapy.

Oral administration of colitis tissue-accumulating porous nanoparticles for ulcerative colitis therapy.

To improve the penetration and accumulation of anti-inflammatory drugs in colitis tissue, we functionalized the surface of porous poly(lactic-co-glycolic acid) nanoparticles (NPs) using pluronic F127 (PF127) and loaded curcumin (CUR) into the resulting NPs to obtain porous PF127-functionalized CUR-loaded NPs (porous PF127-NPs). These NPs had an average hydrodynamic diameter of about 270 nm with a highly monodisperse size distribution, slightly negative surface charge and controllable CUR release profile. It was found that they had good biocompatibility and yielded a much higher cellular uptake rate of CUR than porous CUR-loaded NPs without PF127 modification (porous NPs). In addition, porous PF127-NPs showed a greater capacity to inhibit the major pro-inflammatory cytokines (IL-6, IL-12 and TNF-α) secreted from lipopolysaccharide-activated macrophages than porous NPs and non-porous PF127-NPs. In vivo experiments suggested that porous PF127-NPs achieved the best therapeutic outcomes against ulcerative colitis (UC) in mice compared with porous NPs and non-porous PF127-NPs. Our results clearly demonstrate that these fabricated porous PF127-NPs show a great promise as an efficient CUR nanocarrier for UC therapy.

CD98 siRNA-loaded nanoparticles decrease hepatic steatosis in mice.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid hepatic accumulation. Here, we investigated whether a reduction of CD98 expression mediated by CD98 siRNA-loaded nanoparticles (NPs) could attenuate liver disease markers in a mouse model of NAFLD. NPs were generated using a double emulsion/solvent evaporation technique. Mice fed a high fat diet for 8 weeks to induce fatty liver were treated with vein tail injections of CD98 siRNA-loaded NPs. In vitro, HepG2 treated with CD98 siRNA-loaded NPs showed significant downregulation of CD98 leading to a significant decrease of major pro-inflammatory cytokines and markers. In vivo, CD98 siRNA-loaded NPs strongly decreased all markers of NAFLD, including the blood levels of ALT and lipids accumulation, fibrosis evidence and pro-inflammatory cytokines. In conclusion, our results indicate that CD98 appears to function as a key actor/inducer in NAFLD, and that our NPs approach may offer a new targeted therapeutic for this disease.

Development of a bone targeted thermosensitive liposomal doxorubicin formulation based on a bisphosphonate modified non-ionic surfactant.

Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.