Jingjing Xie

Innovative silica nanomaterials have made the significant advancements in curative therapy against cancers with multidrug resistance (MDR). The study on different‐nanostructured mesoporous silica nanoparticles (MSNs) with discrepant pore sizes affecting biomacromolecules in resisting cancer MDR hasn't been reported yet. In this study, a systematic comparison of 6 nm‐pore sized hollow‐structured MSNs (HMSNs) and 10 nm‐pore sized dendrimers‐structured MSNs (LMSNs) for delivering Bcl‐2‐functional converting peptide (N9) or doxorubicin (DOX) to overcome cancer MDR is comprehensively carried out both in in vitro and in vivo resistant tumor models. The results show that both LMSNs and HMSNs exert no significant difference in delivering DOX to treat drug‐resistant cancers. However, compared with N9@HMSNs, N9@LMSNs display the increased loading efficiency, the improved cell‐penetrative capability, the higher cancer cell apoptosis effect, the enhanced tumor accumulation and retention efficiency, and the final elevated tumor inhibition efficiency. Unexpectedly, naked LMSNs without surface modification especially at high dosage produce relatively more serious toxicity than HMSNs whatever in cells, zebrafish embryo or mice models. Collectively, the data provide the sufficient theoretical evidence that LMSNs might be a better choice for delivering biomacromolecules to treat resistant cancers after appropriate surface functionalization such as with PEGylation to weaken its intrinsic toxicity.

This paper explores the problem of distributed circular formation control for networked dynamic nonholonomic vehicles. The topology among the networked vehicles is described by a directed graph. A backstepping-based distributed control law, which requires each vehicle to use local measurement and communication, is proposed for the kinematic and dynamic models of nonholonomic vehicles. The study demonstrates that all vehicles can achieve global convergence to a predetermined circular trajectory while revolving around the target. Furthermore, they can also globally converge to a desired formation with appropriate spacing along the circular path. Finally, a simulation example is presented to illustrate the result.

Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.

Background/Objective: Circulating tumor cells (CTCs) are known as the root of cancer metastasis. Capture and inhibition of CTCs may prevent metastasis. Due to the rarity of CTCs in vivo, the current technology about CTCs capture is still challenging. The aim of our study was to conjugate the enhanced biostable double-strand (ds) circular aptamer (dApR) with dendrimers for capturing and restraining CTCs in vitro and in vivo. Methods: CEM-targeting aptamer (Ap) was looped by ligation after phosphorylation to form circular ds aptamer dApR, which was then conjugated to dendrimers by biotin-streptavidin affinity reaction and named as G-dApR. The physicochemical properties of G-dApR were characterized by using PAGE gel electrophoresis, UV, DLS, AFM, fluorophotometer and laser confocal microscope. Biostability of G-dApR was also analyzed by gel electrophoresis. Confocal microscopy and flow cytometry were then performed to determine the binding specificity of G-dApR to CEM cells and the captured CTCs in mice and in human blood. Apoptosis of the captured cells was finally evaluated by using MTT assay, DAPI staining, AO/EB staining, cell cycle analysis and Annexin V-FITC/PI staining. Results: Physicochemical characterization demonstrated the entity of dApR and G-dApR, and the nano-size of G-dApR (about 180 nm in aqueous phase). G-dApR exhibited the excellent biostability that confers their resistance to nuclease-mediated biodegradation in serum for at least 6 days. In our established CTCs model, we found that G-dApR could specifically and sensitively capture CTCs not non-target cells even in the presence of millions of interfering cells (10⁸), in mice and in human blood. Finally, the activity of captured CTCs was significantly down-regulated by G-dApR, resulting in apoptosis. Conclusion: We created the enhanced biostable dApR-coated dendrimers (G-dApR) that could specifically capture and restrain CTCs in vitro and in vivo for preventing CTC-mediated cancer metastasis.