Exploring Efficient Dual-Phase Emissive Fluorophores with High Mobility by Integrating a Rigid Donor and Flexible Acceptor.

Developing luminogens with a high emission efficiency in both single-molecule and aggregate states, as well as high mobility, shows promise for advancing the iteration and update of organic optoelectronic materials. However, achieving a delicate balance between the plane configuration of luminophores and the strong exciton interactions of aggregates is a formidable task from the molecular design perspective. This dilemma was overcome by integrating a rigid donor and flexible acceptor to establish donor-acceptor (D-A) type emitters. The π-conjugate-extended donor ensures the substantial planarity of these molecules, allowing strong emission in solution with photoluminescence quantum yield values of 86% and 75%. Furthermore, the restricted molecular motion of the aggregation-induced emission moiety and the formation of J-aggregates reduce the quenching effect, leading to a high emissive efficiency of 85% and 91% in the aggregate state. The mildly distorted D-A geometry builds moderate electrostatic interaction, resulting in high mobility with µM,h of 7.12 × 10-5 and 3.27 × 10-4 cm2/V s. Additionally, an improved synthesized procedure for terminal E-configured acrylonitrile with metal-free and concise reaction conditions is presented. The successful application of the synthesized compounds in organic light-emitting diode devices demonstrates the practicability of the molecular design strategy with connecting a rigid donor and flexible acceptor.

Highly Solvent Resistant Small-Molecule Hole-Transporting Materials for Efficient Perovskite Quantum Dot Light-Emitting Diodes.

Perovskite quantum dot light-emitting diodes (Pe-QLEDs) have been shown as promising candidates for next-generation displays and lightings due to their unique feature of wide color gamut and high color saturation. Hole-transporting materials (HTMs) play crucial roles in the device performance and stability of Pe-QLEDs. However, small-molecule HTMs have been less studied in Pe-QLEDs due to their poor solvent resistance and low hole mobility. In this work, three novel small-molecule HTMs employing benzimidazole as the center core, named X4, X5, and X6, were designed and synthesized for application in Pe-QLEDs. One of the tailored HTM-X6 exhibits excellent solvent resistant ability to the perovskite quantum dot (QD) inks due to its proper solubility and low surface energy. Our result clearly demonstrated that the synergistic effect of poor solubility and low surface energy facilitates the achievement of good solvent resistance to perovskite QD inks. As a result, a promising maximal external quantum efficiency (EQE) of 14.1% is achieved in X6-based CsPbBr3 Pe-QLEDs, which is much higher than that of X4 (9.16%) and X5 (6.60%)-based devices, which is comparable to the PTAA reference (EQE ∼ 15.8%) under the same conditions. To the best of our knowledge, this is the first example that a benzimidazole-based small-molecule HTM demonstrated a good application in Pe-QLEDs. Our work provides new guidance for the rational design of small-molecule HTMs with high solvent resistance for efficient Pe-QLEDs and other photoelectronic devices.

Sequential Multistep Excited-State Structural Transformations in N,N'-Diphenyl-dihydrodibenzo[a,c]phenazine Fluorophores.

We demonstrate that a single polycyclic π-scaffold can undergo sequential multistep excited-state structural evolution along the bent, planar, and twisted conformers, which coexist to produce intrinsic multiple fluorescence emissions in room-temperature solution. By installing a methyl or trifluoromethyl group on the ortho-site of N,N'-diphenyl-dihydrodibenzo[a,c]phenazine (DPAC), the enhanced steric effects change the fluorescence emission of DPAC from a dominant red band to well-resolved triple bands. The ultra-broadband triple emissions of ortho-substituted DPACs range from ≈350 to ≈850 nm, which is unprecedented for small fluorophores with molecular weight of <500. Ultrafast spectroscopy and theoretical calculations clearly reveal that the above dramatic changes originate from the influence of steric hindrance on the shape of excited state potential energy surface (S1 PES). Compared to the steep S1 PES of parental DPAC, the introduction of ortho-substituent is shown to make the path of structural evolution in S1 wider and flatter, so the ortho-substituted derivatives exhibit slower structural transformations from bent to planar and then to twisted forms, yielding intrinsic triple emission. The results provide the proof of concept that the bent, planar, and twisted emissive states can coexist in the same S1 PES, which greatly expand the fundamental understanding of the excited-state structural relaxation.

Predicting Extrathyroidal Extension in Papillary Thyroid Carcinoma Using a Clinical-Radiomics Nomogram Based on B-Mode and Contrast-Enhanced Ultrasound.

Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. PTC patients with extrathyroidal extension (ETE) are associated with poor prognoses. The preoperative accurate prediction of ETE is crucial for helping the surgeon decide on the surgical plan. This study aimed to establish a novel clinical-radiomics nomogram based on B-mode ultrasound (BMUS) and contrast-enhanced ultrasound (CEUS) for the prediction of ETE in PTC. A total of 216 patients with PTC between January 2018 and June 2020 were collected and divided into the training set (n = 152) and the validation set (n = 64). The least absolute shrinkage and selection operator (LASSO) algorithm was applied for radiomics feature selection. Univariate analysis was performed to find clinical risk factors for predicting ETE. The BMUS Radscore, CEUS Radscore, clinical model, and clinical-radiomics model were established using multivariate backward stepwise logistic regression (LR) based on BMUS radiomics features, CEUS radiomics features, clinical risk factors, and the combination of those features, respectively. The diagnostic efficacy of the models was assessed using receiver operating characteristic (ROC) curves and the DeLong test. The model with the best performance was then selected to develop a nomogram. The results show that the clinical-radiomics model, which is constructed by age, CEUS-reported ETE, BMUS Radscore, and CEUS Radscore, showed the best diagnostic efficiency in both the training set (AUC = 0.843) and validation set (AUC = 0.792). Moreover, a clinical-radiomics nomogram was established for easier clinical practices. The Hosmer-Lemeshow test and the calibration curves demonstrated satisfactory calibration. The decision curve analysis (DCA) showed that the clinical-radiomics nomogram had substantial clinical benefits. The clinical-radiomics nomogram constructed from the dual-modal ultrasound can be exploited as a promising tool for the pre-operative prediction of ETE in PTC.

Clinical-Radiomics Nomogram Based on Contrast-Enhanced Ultrasound for Preoperative Prediction of Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma.

This study aimed to establish a new clinical-radiomics nomogram based on ultrasound (US) for cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). We collected 211 patients with PTC between June 2018 and April 2020, then we randomly divided these patients into the training set (n = 148) and the validation set (n = 63). 837 radiomics features were extracted from B-mode ultrasound (BMUS) images and contrast-enhanced ultrasound (CEUS) images. The maximum relevance minimum redundancy (mRMR) algorithm, least absolute shrinkage and selection operator (LASSO) algorithm, and backward stepwise logistic regression (LR) were applied to select key features and establish a radiomics score (Radscore), including BMUS Radscore and CEUS Radscore. The clinical model and clinical-radiomics model were established using the univariate analysis and multivariate backward stepwise LR. The clinical-radiomics model was finally presented as a clinical-radiomics nomogram, the performance of which was evaluated by the receiver operating characteristic curves, Hosmer-Lemeshow test, calibration curves, and decision curve analysis (DCA). The results show that the clinical-radiomics nomogram was constructed by four predictors, including gender, age, US-reported LNM, and CEUS Radscore. The clinical-radiomics nomogram performed well in both the training set (AUC = 0.820) and the validation set (AUC = 0.814). The Hosmer-Lemeshow test and the calibration curves demonstrated good calibration. The DCA showed that the clinical-radiomics nomogram had satisfactory clinical utility. The clinical-radiomics nomogram constructed by CEUS Radscore and key clinical features can be used as an effective tool for individualized prediction of cervical LNM in PTC.

Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy.

Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving optimal drug-delivery efficacy. Here, we develop ligand-switchable nanoparticles which resemble viral unique surfaces, enabling them to fully display diverse functions. The nanoparticles are modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). Once orally administered, the acidic environments trigger the extension of Pep from surface in a virus-like manner, enabling Pep/Gal-PNPs to traverse intestinal barriers efficiently. Subsequently, Gal is exposed by Pep folding at physiological pH, thereby allowing the specific targeting of Pep/Gal-PNPs to the liver. As a proof-of-concept, insulin-loaded Pep/Gal-PNPs are fabricated which exhibit effective intestinal absorption and excellent hepatic deposition of insulin. Crucially, Pep/Gal-PNPs increase hepatic glycogen production by 7.2-fold, contributing to the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieving full potential of diverse ligands on multifunctional nanoparticles.

An Improved Synthesis of Water-Soluble Dual Fluorescence Emission Carbon Dots from Holly Leaves for Accurate Detection of Mercury Ions in Living Cells.

BACKGROUND: Carbon dots (CDs) emitting near-infrared fluorescence were recently synthesized from green leaves. However, the Hg2+ detection of CDs was limited because of the insufficient water solubility, low fluorescence and poor stability. METHODS: Dual fluorescence emission water-soluble CD (Dual-CD) was prepared through a solvothermal method from holly leaves and low toxic PEI1.8k. PEG was further grafted onto the surface to improve the water solubility and stability. RESULTS: The Dual-CD solution can emit 487 nm and 676 nm fluorescence under single excitation and exhibit high quantum yield of 16.8%. The fluorescence at 678 nm decreased remarkably while the emission at 470 nm was slightly affected by the addition of Hg2+. The ratiometric Hg2+ detection had a wide linear range of 0-100 µM and low detection limit of 14.0 nM. In A549 cells, there was a good linear relation between F487/F676 and the concentration of Hg2+ in the range of 0-60 µM; the detection limit was 477 nM. Furthermore, Dual-CD showed visual fluorescence change under Hg2+. CONCLUSION: Dual-CD has ratiometric responsiveness to Hg2+ and can be applied for quantitative Hg2+ detection in living cells.

MT1-MMP-Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy.

Promoting tumor angiogenesis effectively and specifically to resolve tumor-associated hypoperfusion holds promise for improving pancreatic cancer therapy. Herein, a doxorubicin (DOX) loaded smart liposome, MC-T-DOX, is constructed, that carries appropriately low-density cilengitide, an αvß3 integrin-specific Arg-Gly-Asp (RGD)-mimetic cyclic peptide, via a membrane type 1-matrix metalloproteinase (MT1-MMP) cleavable peptide. After being administered systemically in a hypoperfused pancreatic cancer mouse model at a low dose of cilengitide, the proangiogenic activity of MC-T-DOX is specifically "turned on" in tumor vessels through cleavage by MT1-MMP on tumor endothelial cells to release cilengitide. This locally released cilengitide increases tumor blood perfusion, thereby improving the accumulation and distribution of MC-T-DOX in the tumor site. The loaded-DOX then displays enhanced penetration and increased cellular uptake upon heat-triggered release from MC-T-DOX in the tumor interstitium, contributing to the improved tumor therapy efficacy. Therefore, the strategy of combining the modulation of tumor vascular promotion with smart nanodrug delivery represents a promising approach to improving drug delivery and therapeutic efficacy in a wide range of hypoperfused tumors.

Silicone elastomer gel impregnated with 20(S)-protopanaxadiol-loaded nanostructured lipid carriers for ordered diabetic ulcer recovery.

Inefficient diabetic ulcer healing and scar formation remain a challenge worldwide, owing to a series of disordered and dynamic biological events that occur during the process of healing. A functional wound dressing that is capable of promoting ordered diabetic wound recovery is eagerly anticipated. In this study, we designed a silicone elastomer with embedded 20(S)-protopanaxadiol-loaded nanostructured lipid carriers (PPD-NS) to achieve ordered recovery in scarless diabetic ulcer healing. The nanostructured lipid carriers were prepared through an emulsion evaporation-solidification method and then incorporated into a network of silicone elastomer to form a unique nanostructured lipid carrier-enriched gel formulation. Interestingly, the PPD-NS showed excellent in vitro anti-inflammatory and proangiogenic activity. Moreover, in diabetic mice with full-thickness skin excision wound, treatment with PPD-NS significantly promoted in vivo scarless wound healing through suppressing inflammatory infiltration in the inflammatory phase, promoting angiogenesis during the proliferation phase, and regulating collagen deposition in the remodeling phase. Hence, this study demonstrates that the developed PPD-NS could facilitate ordered diabetic wound recovery via multifunctional improvement during different wound-healing phases. This novel approach could be promising for scarless diabetic wound healing.

Cancer-Cell-Membrane-Coated Nanoparticles with a Yolk-Shell Structure Augment Cancer Chemotherapy.

Despite rapid advancements in antitumor drug delivery, insufficient intracellular transport and subcellular drug accumulation are still issues to be addressed. Cancer cell membrane (CCM)-camouflaged nanoparticles (NPs) have shown promising potential in tumor therapy due to their immune escape and homotypic binding capacities. However, their efficacy is still limited due to inefficient tumor penetration and compromised intracellular transportation. Herein, a yolk-shell NP with a mesoporous silica nanoparticle (MSN)-supported PEGylated liposome yolk and CCM coating, CCM@LM, was developed for chemotherapy and exhibited a homologous tumor-targeting effect. The yolk-shell structure endowed CCM@LM with moderate rigidity, which might contribute to the frequent transformation into an ellipsoidal shape during infiltration, leading to facilitated penetration throughout multicellular spheroids in vitro (up to a 23.3-fold increase compared to the penetration of membrane vesicles). CCM@LM also exhibited a cellular invasion profile mimicking an enveloped virus invasion profile. CCM@LM was directly internalized by membrane fusion, and the PEGylated yolk (LM) was subsequently released into the cytosol, indicating the execution of an internalization pathway similar to that of an enveloped virus. The incoming PEGylated LM further underwent efficient trafficking throughout the cytoskeletal filament network, leading to enhanced perinuclear aggregation. Ultimately, CCM@LM, which co-encapsulated low-dose doxorubicin and the poly(ADP-ribose) polymerase inhibitor, mefuparib hydrochloride, exhibited a significantly stronger antitumor effect than the first-line chemotherapeutic drug Doxil. Our findings highlight that NPs that can undergo facilitated tumor penetration and robust intracellular trafficking have a promising future in cancer chemotherapy.

Chain-Length- and Saturation-Tuned Mechanics of Fluid Nanovesicles Direct Tumor Delivery.

Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules (i.e., the acyl chain length and saturation) are known to affect the mechanical properties of SUVs and consequently regulate their biological behaviors and functions, the underlying mechanism remains elusive. Here, we combined theoretical modeling and experimental investigation to probe the mechanical behaviors of SUVs with different lipid compositions. The membrane bending rigidity of SUVs increased with increasing chain length and saturation, resulting in differences in the vesicle rigidity and deformable capacity. Furthermore, we tested the tumor delivery capacity of liposomes with low, intermediate, and high rigidity as typical models for SUVs. Interestingly, liposomes with intermediate rigidity exhibited better tumor extracellular matrix diffusion and multicellular spheroid (MCS) penetration and retention than that of their stiffer or softer counterparts, contributing to improved tumor suppression. Stiff SUVs had superior cellular internalization capacity but intermediate tumor delivery efficacy. Stimulated emission depletion microscopy directly showed that the optimal formulation was able to transform to a rod-like shape in MCSs, which stimulated fast transport in tumor tissues. In contrast, stiff liposomes hardly deformed, whereas soft liposomes changed their shape irregularly, which slowed their MCS penetration. Our findings introduce special perspectives from which to map the detailed mechanical properties of SUVs with different compositions, provide clues for understanding the biological functions of SUVs, and suggest that liposome mechanics may be a design parameter for enhancing drug delivery.

Temperature- and rigidity-mediated rapid transport of lipid nanovesicles in hydrogels.

Lipid nanovesicles are widely present as transport vehicles in living organisms and can serve as efficient drug delivery vectors. It is known that the size and surface charge of nanovesicles can affect their diffusion behaviors in biological hydrogels such as mucus. However, how temperature effects, including those of both ambient temperature and phase transition temperature (Tm), influence vehicle transport across various biological barriers outside and inside the cell remains unclear. Here, we utilize a series of liposomes with different Tm as typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when their Tm is around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes with Tm around body temperature (i.e., ∼37 °C) exhibit enhanced cellular uptake in mucus-secreting epithelium and show significant improvement in oral insulin delivery efficacy in diabetic rats compared with those with higher or lower Tm Molecular-dynamics (MD) simulations and superresolution microscopy reveal a temperature- and rigidity-mediated rapid transport mechanism in which the liposomes frequently deform into an ellipsoidal shape near the phase transition temperature during diffusion in biological hydrogels. These findings enhance our understanding of the effect of temperature and rigidity on extracellular and intracellular functions of nanovesicles such as endosomes, exosomes, and argosomes, and suggest that matching Tm to ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors.

Protein Corona Liposomes Achieve Efficient Oral Insulin Delivery by Overcoming Mucus and Epithelial Barriers.

Oral delivery of peptide/protein drugs has attracted worldwide attention due to its good patient compliance and convenience of administration. Orally administered nanocarriers always encounter the rigorous defenses of the gastrointestinal tract, which mainly consist of mucus and epithelium barriers. However, diametrically opposite surface properties of nanocarriers are required for good mucus penetration and high epithelial uptake. Here, bovine serum albumin (BSA) is adsorbed to cationic liposomes (CLs) to form protein corona liposomes (PcCLs). The aim of using PcCLs is to conquer the mucus and epithelium barriers, eventually improving the oral bioavailability of insulin. Investigations using in vitro and in vivo experiments show that the uptake amounts and transepithelial permeability of PcCLs are 3.24- and 7.91-fold higher than that of free insulin, respectively. Further study of the behavior of PcCLs implies that BSA corona can be shed from PcCLs as they cross the mucus layer, which results in the exposure of CLs to improve the transepithelial transport. Intrajejunal administration of PcCLs in type I diabetic rats produces a remarkable hypoglycemic effect and increases the oral bioavailability up to 11.9%. All of these results imply that PcCLs may provide a new insight into the method for oral insulin delivery by overcoming the multiple barriers.

Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers.

To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.

Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery.

Oral absorption of protein/peptide-loaded nanoparticles is often limited by multiple barriers of the intestinal epithelium. In addition to mucus translocation and apical endocytosis, highly efficient transepithelial absorption of nanoparticles requires successful intracellular trafficking, especially to avoid lysosomal degradation, and basolateral release. Here, the functional material, deoxycholic acid-conjugated chitosan, is synthesized and loaded with the model protein drug insulin into deoxycholic acid-modified nanoparticles (DNPs). The DNPs designed in this study are demonstrated to overcome multiple barriers of the intestinal epithelium by exploiting the bile acid pathway. In Caco-2 cell monolayers, DNPs are internalized via apical sodium-dependent bile acid transporter (ASBT)-mediated endocytosis. Interestingly, insulin degradation in the epithelium is significantly prevented due to endolysosomal escape of DNPs. Additionally, DNPs can interact with a cytosolic ileal bile acid-binding protein that facilitates the intracellular trafficking and basolateral release of insulin. In rats, intravital two-photon microscopy also reveals that the transport of DNPs into the intestinal villi is mediated by ASBT. Further pharmacokinetic studies disclose an oral bioavailability of 15.9% in type I diabetic rats after loading freeze-dried DNPs into enteric-coated capsules. Thus, deoxycholic acid-modified chitosan nanoparticles can overcome multiple barriers of the intestinal epithelium for oral delivery of insulin.

Thermosensitive Liposomal Codelivery of HSA-Paclitaxel and HSA-Ellagic Acid Complexes for Enhanced Drug Perfusion and Efficacy Against Pancreatic Cancer.

Fibrotic stroma and tumor-promoting pancreatic stellate cells (PSCs), critical characters in the pancreatic ductal adenocarcinoma (PDA) microenvironment, promote a tumor-facilitating environment that simultaneously prevents drug penetration into tumor foci and stimulates tumor growth. Nab-PTX, a human serum albumin (HSA) nanoparticle of paclitaxel (PTX), indicates enhanced matrix penetration in PDA probably due to its small size in vivo and high affinity of HSA with secreted protein acidic and rich in cysteine (SPARC), overexpressed in the PDA stroma. However, this HSA nanoparticle shows poor drug blood retention because of its weak colloidal stability in vivo, thus resulting in insufficient drug accumulation within tumor. Encapsulating HSA nanoparticles into the internal aqueous phase of ordinary liposomes improves their blood retention and the following tumor accumulation, but the large 200 nm size and shielding of HSA in the interior might make it difficult for this hybrid nanomedicine to penetrate the fibrotic PDA matrix and promote bioavailability of the payload. In our current work, we prepared ∼9 nm HSA complexes with an antitumor drug (PTX) and an anti-PSC drug (ellagic acid, EA), and these two HSA-drug complexes were further coencapsulated into thermosensitive liposomes (TSLs). This nanomedicine was named TSL/HSA-PE. The use of TSL/HSA-PE could improve drug blood retention, and upon reaching locally heated tumors, these TSLs can rapidly release their payloads (HSA-drug complexes) to facilitate their further tumor accumulation and matrix penetration. With superior tumor accumulation, impressive matrix penetration, and simultaneous action upon tumor cells and PSCs to disrupt PSCs-PDA interaction, TSL/HSA-PE treatment combined with heat exhibited strong tumor growth inhibition and apoptosis in vivo.

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials.

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.

Rotation-Facilitated Rapid Transport of Nanorods in Mucosal Tissues.

Mucus is a viscoelastic gel layer that typically protects exposed surfaces of the gastrointestinal (GI) tract, lung airways, and other mucosal tissues. Particles targeted to these tissues can be efficiently trapped and removed by mucus, thereby limiting the effectiveness of such drug delivery systems. In this study, we experimentally and theoretically demonstrated that cylindrical nanoparticles (NPs), such as mesoporous silica nanorods and calcium phosphate nanorods, have superior transport and trafficking capability in mucus compared with spheres of the same chemistry. The higher diffusivity of nanorods leads to deeper mucus penetration and a longer retention time in the GI tract than that of their spherical counterparts. Molecular simulations and stimulated emission of depletion (STED) microscopy revealed that this anomalous phenomenon can be attributed to the rotational dynamics of the NPs facilitated by the mucin fibers and the shear flow. These findings shed new light on the shape design of NP-based drug delivery systems targeted to mucosal and tumor sites that possess a fibrous structure/porous medium.

Advances in the transepithelial transport of nanoparticles.

The intestinal epithelium represents a barrier to the delivery of nanoparticles (NPs). It prevents intact NPs from efficiently crossing the mucosa to access the circulation, thus limiting the successful application of NP-based oral drug delivery. Recent advances in nanotechnology have provided promising solutions to this challenge. This review describes the potential intestinal absorption pathways of NPs, including the transenterocytic pathway, paracellular pathway and M-cell-mediated pathway. NP properties that influence transcytosis are summarized; and the biodistribution of NPs after oral absorption is described and the future prospects of novel NPs are explored.