Wet age-related macular degeneration (wAMD), characterized by choroidal neovascularization (CNV), faces a clinical challenge of diminishing efficacy during long-term anti-VEGF monotherapy. An AI-assisted analytical framework pinpointed impaired retinal pigment epithelium (RPE) autophagy and a pro-inflammatory microenvironment driven by retinal microglia-recruited monocytes as co-conspirators in CNV progression. To tackle these dual culprits, we developed an intravitreal injectable hydrogel (Rab&BCL-M@G) that co-encapsulates ranibizumab (Rab) and a small-sized baicalin-loaded microemulsion (BCL-M), enabling controlled and sustained co-delivery of both agents to the retina for over 14 days. Guided by the AI-identified targets, we demonstrated that baicalin promoted dysfunctional mitochondria clearance via the AKT2-PGC-1α-mediated autophagic flux and suppressed monocyte recruitment by disrupting microglial CCL4 signaling. This two-pronged action ameliorated inflammation and angiogenesis, synergizing with Rab. In a laser-induced wAMD mouse model, a single intravitreal injection of Rab&BCL-M@G sustainably reduced CNV area, promoted repair, restored autophagy, and diminished microglial infiltration. Crucially, subsequent wet-lab validation confirmed a positive pathological correlation among defective autophagy, inflammation, and angiogenesis, thereby closing the loop from computational prediction to experimental verification and explaining suboptimal long-term performance after Rab monotherapy. This study proposes a promising synergistic strategy, advancing wAMD therapy through precision delivery and AI-informed mechanism discovery.

ETHNOPHARMACOLOGICAL RELEVANCE:Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart.AIM OF THE STUDY:The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation.MATERIALS AND METHODS:The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed.RESULTS:The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1β, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1β, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites.CONCLUSION:Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1β, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.

Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.

Autophagic dysfunction-induced deterioration of the retinal microenvironment drives the progression of wet age-related macular degeneration (wAMD). The efficacy of single-target anti-VEGF antibodies in treating wAMD has long been suboptimal due to the intricate interplay between autophagy dysfunction, oxidative stress, and angiogenesis. Here, we introduce an intravitreal hydrogel depot, named Rab&Rapa-M@G, consisting of rapamycin-loaded microemulsion (Rapa-M, an mTOR inhibitor), ranibizumab (anti-VEGF antibody), and a thermosensitive hydrogel matrix. A single intravitreal injection of Rab&Rapa-M@G can sustainably deliver Rapa-M and ranibizumab to the retinal pigment epithelium for at least 14 days. This formulation significantly improves retinal autophagic flux homeostasis and reduces oxidative stress injury in wAMD mice by modulating the AMPK/mTOR/HIF-1α/VEGF and AMPK/ROS/HO-1/VEGF pathways. Consequently, it synergistically disrupts the “autophagic dysfunction-oxidative stress-angiogenesis” loop, leading to a remarkable reduction in choroidal neovascularization area and retinal damage compared to ranibizumab alone. Notably, the sequential administration of ranibizumab and Rab&Rapa-M@G further enhances the overall anti-wAMD efficacy, achieved through sequential delivery of Rab and Rapa, allowing for a more precise grasp of the treatment window. In conclusion, this hydrogel depot design, with its sequential and sustained delivery of mTOR inhibitors and anti-VEGF antibodies, offers a promising strategy for multi-target synergistic therapy in wAMD.

The insufficient abundance and weak activity of tumour-infiltrating lymphocytes (TILs) are two important reasons for the poor efficacy of PD-1 inhibitors in hepatocellular carcinoma (HCC) treatment. The combined administration of tanshinone IIA (TSA) and astragaloside IV (As) can up-regulate the abundance and activity of TILs by normalising tumour blood vessels and reducing the levels of immunosuppressive factors respectively. For enhancing the efficacy of PD-1 antibody, a magnetic metal-organic framework (MOF) with a homologous tumour cell membrane (Hm) coating (Hm@TSA/As-MOF) is established to co-deliver TSA&As into the HCC microenvironment. Hm@TSA/As-MOF is a spherical nanoparticle and has a high total drug-loading capacity of 16.13 wt%. The Hm coating and magnetic responsiveness of Hm@TSA/As-MOF provide a homologous-magnetic dual-targeting, which enable Hm@TSA/As-MOF to counteract the interference posed by ascites tumour cells and enhance the precision of targeting solid tumours. Hm coating also enable Hm@TSA/As-MOF to evade immune clearance by macrophages. The release of TSA&As from Hm@TSA/As-MOF can be accelerated by HCC microenvironment, thereby up-regulating the abundance and activity of TILs to synergistic PD-1 antibody against HCC. This study presents a nanoplatform to improve the efficacy of PD-1 inhibitors in HCC, providing a novel approach for anti-tumour immunotherapy in clinical practice.

>Drug carriers are systems that alter how a drug enters the body and its distribution within the body, control the rate of drug release and deliver the drug to the target organ [1] . Systems that use drug carriers to control the release of drugs have received widespread attention as they can improve drug utilization, safety and efficacy, and thus can reduce the frequency of drug administration [2] .

Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age-related macular degeneration (wAMD). Here, a microemulsion-doped hydrogel (Bor/PT-M@TRG) is engineered as an intravitreal depot composing of temperature-responsive hydrogel (TRG) and borneol-decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)-coloaded microemulsions (Bor/PT-M). Bor/PT-M@TRG, functioning as the "ammunition depot", resides in the vitreous and continuously releases Bor/PT-M as the therapeutic "bullet", enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT-M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress-induced damage in vivo. Combinational PF&TMP regulates the "reactive oxygen species/nuclear factor erythroid-2-related factor 2/heme oxygenase-1" pathway and blocks the "hypoxia inducible factor-1α/vascular endothelial growth factor" signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography-mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE-19 cells, in vivo eye balls, and ex vivo section/retina-choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT-M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.

The treatment of tumors continues to be significantly challenging. The presence of multiple modalities, including surgery, radiation, chemotherapy and immunotherapy, the therapeutic outcomes remain limited and are often associated with adverse effects and inconsistent efficacy across cancer types. Recent studies have highlighted the potential of active components from traditional Chinese medicine (TCM) for their anti-cancer properties, which are attributable to multi-targeted mechanisms and broad pharmacological actions. Despite this potential, TCM-derived compounds are commonly limited by poor water solubility, low bioavailability, and suboptimal targeting. Currently, it is believed that advances in nanotechnology could address these limitations. Nanoparticles (NPs), which possess properties such as enhanced bioavailability, controlled release and precise targeting, have been used to improve the therapeutic efficacy of TCM components in cancer therapy. This review discusses the use of NPs for the delivery of active TCM compounds via organic-inorganic nanocarriers, highlighting innovative strategies that enhance the effectiveness of TCM-based anti-tumor components to provide insights into improving clinical outcomes while advancing the modernization and global application of TCM in oncology.

Background: Iron-based nanocarriers have demonstrated potential in redirecting tumor associated macrophages (TAMs) polarization towards the M1 phenotype, critical for activating the tumor microenvironment (TME) in triple negative breast cancer (TNBC). However, their real-world effectiveness is curtailed by insufficient Fe2+/3+ exposure and the absence of suitable synergists in tumors. Methods: We introduce an air bag-embedded iron-based MIL-101 metal-organic frameworks (MOFMIL-101(Fe)) for igniting the TME in TNBC through bubble-driven tumoral codelivery of Fe2+/3+ and lentinan. This system, named HM/Ef/LNT-MOFMIL-101(Fe), features nano-sized MOFMIL-101(Fe) as the core, embedded NaHCO3 as a pH-triggered air bag, electrostatically-adsorbed lentinan forming the inner shell, and a shield shell with 4T1&red blood cell hybrid membrane. Results: HM/Ef/LNT-MOFMIL-101(Fe) can mitigate non-specific capture in the bloodstream but respond to the acidic tumor milieu, rapidly generating a burst of CO2 bubbles to disassemble MOFMIL-101(Fe). Upon entering tumors, lentinan-induced interferon-gamma (IFN-gamma) enable Fe2+/3+ facilitating an enhanced ferroptosis and Fenton-like reaction, pushing TAMs towards M1 polarization via the "IFN-gamma-ferroptosis-ROS-Caspase-3" pathway. Moreover, HM/Ef/LNT-MOFMIL-101(Fe) increases the infiltration of T lymphocytes and decreases regulatory T cells. These cascading immune responses synergistically foster a loop of amplified TME activation based on TAMs M1 polarization, showcasing notable advancements in anticancer effectiveness and promise for various combination therapies. Conclusion: This study utilizes an "embedded air-bag" strategy to achieve strategic codelivery of Fe2+/3+ and lentinan, providing a new tool for engineering the TME.

M1 polarization of tumor-associated macrophages (TAMs) is a promising approach to breaking through therapeutic barriers imposed by the immunosuppressive tumor microenvironment (TME). As a clinically-used immunopotentiator for cancer patients after chemotherapies; however, the immunomodulatory mechanism and potential of polyporus polysaccharide (PPS) remains unclear. Here, we present mannose-decorated PPS-loaded superparamagnetic iron-based nanocomposites (Man/PPS-SPIONs) for synergistic M1 polarization of TAMs and consequent combinational anti-breast cancer therapy. Once internalized by M2-like TAMs, PPS released from Man/PPS-SPIONs induces the M1 polarization via IFN-γ secretion and downstream NF-κB pathway activating. The SPIONs within the nanocomposites mediate a Fenton reaction, producing OH· and activating the subsequent NF-κB/MAPK pathway, further facilitating the M1 polarization. The Man/PPS-SPIONs thereby establish a positive feedback loop of M1 polarization driven by the "IFN-γ-Fenton-NF-κB/MAPK" multi-pathway, leading to a series of anti-tumoral immunologic responses in the TME and holding promising potential in combinational anticancer therapies. Our study offers a new strategy to amplify TME engineering by combinational natural carbohydrate polymers and iron-based materials.

Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Blood-vessel-embolic agents play key role on TACE. In the present work, we reported a Bletilla striata polysaccharide/poly (N-isopropylacrylamide) (BSP/PNIPAM) thermosensitive microemulsion gel loaded with magnetic icaritin (ICT) microemulsion (IS-MEs) as embolic agent (ISBP) for the first time. IS-MEs co-loaded with ICT and superparamagnetic iron oxide nanoparticles (SPIONs) were prepared by water titration method. The particle size of IS-MEs was 27.97 +/- 0.25 nm, encapsulation efficiency was 97.18%, and presented a regular sphere under TEM. BSP/PNIPAM was prepared by free radical polymerization, which has good biocompatibility, excellent procoagulant function and dense microstructure. The low critical solution temperature (LCST) of ISBP was 30 degrees C, which had excellent in vitro injection performance. The microscopic morphology of ISBP was loose and porous, the long-acting sustained-release time could reach 144 h, and the maximum ICT release was (48.6 +/- 8.5) %. IPSBs with SPIONs exhibit desirable imaging properties and macrophage M1 polarization function. During the rabbit renal artery embolization, ISBP showed excellent distal vascular embolization performance and there was no obstruction or adhesion of the catheter. These results suggest that a novel in situ multifunctional traditional Chinese medicine thermosensitive microemulsion gel embolic agent has been developed with a potential application as a liquid embolic solution for TACE.

Sustained retina drug delivery and rational drug combination are considered essential for enhancing the efficacy of therapy for wet age-related macular degeneration (wAMD) due to the conservative structure of the posterior ocular segment and the multi-factorial pathological mechanism. Designing a drug co-delivery system that can simultaneously achieve deep penetration and long-lasting retention in the vitreous is highly desired, yet remains a huge challenge. In this study, we fabricated Bor/RB-M@TRG as an intravitreal-injectable hydrogel depot for deep penetration into the posterior ocular segment and long-lasting distribution in the retinal pigment epithelium (RPE) layer. The Bor/RB-M@TRG consisted of borneol-decorated rhein and baicalein-coloaded microemulsions (Bor/RB-M, the therapy entity) and a temperature-responsive hydrogel matrix (the intravitreal depot). Bor/RB-M exhibited the strongest in vitro anti-angiogenic effects among all the groups studied, which is potentially associated with improved cellular uptake, as well as the synergism of rhein and baicalein, acting via anti-angiogenic and anti-oxidative stress pathways, respectively. Importantly, a single intravitreal (IVT) injection with Bor/RB-M@TRG displayed significant inhibition against the CNV of wAMD model mice, compared to all other groups. Particularly, coumarin-6-labeled Bor/RB-M@TRG (Bor/C6-M@TRG) could not only deeply penetrate into the retina but also stably accumulate in the RPE layer for at least 14 days. Our design integrates the advantages of borneol-decorated microemulsions and hydrogel depots, offering a promising new approach for clinically-translatable retinal drug delivery and synergistic anti-wAMD treatment.

Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC). However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function. In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment. We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33.77 wt %) and good immune escape. Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs. In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84.15% and prolonged the survival time of mice. Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.

BACKGROUND:Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.METHODS:In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the "one-step micro-molding" method for boosted transdermal and tumoral delivery of cannabidiol (CBD).RESULTS:Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a "one stone, two birds" strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.CONCLUSIONS:This study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.

Background:Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods:The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results:The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion:Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.

随着纳米医学、生物医学、材料学等学科的融合发展,铁基纳米材料在肿瘤免疫调节和联合抗肿瘤治疗领域正在吸引研究者的目光.铁基纳米材料可触发肿瘤细胞铁死亡,诱导免疫原性细胞死亡,激活肿瘤免疫微环境,作为肿瘤疫苗载体等,具备联合化疗、免疫治疗等提高抗肿瘤综合效能的潜力和可行性.此外,铁基纳米材料可作为核磁共振成像(MRI)造影剂用于肿瘤诊断,其磁靶向性、磁热性等特性使其在靶向热疗方面同样具有较大的潜力.近年来仿生化的设计赋予铁基纳米材料更优的肿瘤靶向性、体内免疫清除豁免、肿瘤免疫调节等功能.该文对铁基纳米材料在肿瘤治疗及应用的进展进行分类综述,并提出了目前面临的挑战以及可能的解决方案.

Neovascular age-related macular degeneration (nAMD) is a leading global cause of blindness characterized by vascular endothelial growth factor (VEGF)-mediated choroidal neovascularization (CNV), in which aberrant pathological angiogenesis extends from the choriocapillaris into the subretinal region. However, the lifelong regime of intraocular anti-VEGF agents, as the front-line treatment for excessive angiogenesis, is not effective for all patients and can induce devastating ocular complications. Thus, it is crucial to develop an available, durable, and affordable drug system capable of overcoming ocular obstacles and enabling the sustained release of a drug to target CNV. Owing to its multitarget properties, tetramethylpyrazine (TMP) has been widely used in clinics for its anti-angiogenic, anti-inflammatory, antioxidant, and anti-fibrotic effects. Yet, its potential clinical use in ocular disorders has been hindered by its lipophilic properties and poor absorption. Herein, we developed and optimized an injectable thermosensitive polymeric hydrogel using the solvent evaporation drying method and the "cold" approach in turn for the controlled release and high drug-loading of TMP nanoparticles, facilitating the sustained release of TMP both in vitro and in vivo. The hydrogel-encapsulated TMP nanocrystals (NCs) were synthesized and characterized by zeta potential, dynamic light scattering, scanning and transmission electron microscopy, and rheometer. The payload of the hydrophobic drug TMP to the symmetrical poly(ethylene glycol)block-poly(propylene glycol)-block-poly(ethylene glycol) hydrogel (TMP-NCs-gel) had a porous structure (pore size, 10-200 mm), and the transparent in situ hydrogel system immediately transitioned from the liquid to gel phase when the phase transition temperature was reached. We also demonstrated that the TMP-NCs-gel ameliorated abnormal angiogenesis and repressed photoreceptor apoptosis in vivo without inducing toxicity. Furthermore, the TMP-NCs-gel were observed to accumulate in CNV lesions in vivo, confirming their targeting characterization. Overall, this advanced formulation, combining TMP and an in situ gel system, is promising for AMD treatment and may represent an effective therapeutic strategy for patients with CNV.

血管栓塞术是临床介入治疗动脉瘤、动静脉畸形和实体瘤等疾病的常用手段,栓塞剂是影响栓塞疗效的重要因素.目前有线圈、微球和Onyx等数种栓塞剂进入临床应用,但仍存在一些治疗局限:如血管穿透能力弱、易于聚集、机械性能差、黏附导管及有毒溶剂参与等.近年来,大量研究发现原位凝胶在血管栓塞领域具有良好的应用前景,其低黏度前体溶液注射到靶向血管后,可通过物理交联和/或化学交联发生溶胶-凝胶转变等形成水凝胶阻断血流,并具有优异的载药缓释性能.本文汇总了近10年来可注射的原位凝胶血管栓塞剂的研究进展,并对其发展前景进行讨论,以期为未来新型栓塞剂的开发提供参考.

Combinational icaritin (IC) and coix seed oil (CSO) holds promising potential in the treatment of hepatocellular carcinoma. However, traditional cocktail therapy is facing difficulties to optimize the synergistic antitumor efficacy due to the asynchronous pharmacokinetics. Therefore, we developed an icaritin-loaded microemulsion based on coix seed oil (IC-MEs) for improved pharmacokinetics and enhanced antitumor efficacy. The preparation technology of IC-MEs was optimized by the Box-Behnken design and the pharmaceutical properties were characterized in detail. IC-MEs show synergistic antiproliferation against HepG2 cells compared with monotherapy. The mechanism is associated with stronger apoptosis induction via enhancing caspases-3 activity. IC-MEs significantly improve the bioavailability of IC due to the encapsulation of coix oil-based microemulsion and also obtain the desired liver accumulation and elimination. More importantly, IC-MEs exhibit the overwhelming antitumor ability among all of the treatments on the HepG2 xenograft-bearing mice. This study verifies the feasibility of using coix oil-based microemulsion to improve the antitumor effect of water-insoluble components.

Cancer-associated fibroblasts (CAFs) deteriorate tumor microenvironment (TME) and hinder intra-tumoral drug delivery. Direct depleting CAFs exists unpredictable risks of tumor metastasis. Epithelial-mesenchymal transition (EMT) is a critical process of CAFs converted from hepatic stellate cells during hepatocellular tumorigenesis; however, until now the feasibility of reversing EMT to battle hepatocellular carcinoma has not been comprehensively explored. In this study, we report a CFH peptide (CFHKHKSPALSPVGGG)-decorated liposomal oxymatrine (CFH/OM-L) with a high affinity to Tenascin-C for targeted inactivating CAFs through reversing EMT, which is verified by the upregulation of E-cadherin and downregulation of vimentin, N-cadherin, and snail protein in vivo and in vitro. After the combination with icaritin-loaded lipid complex, CFH/OM-L obviously boosts the comprehensive anticancer efficacy in both 3D tumor spheroids and stromal-rich tumor xenograft nude mouse models. The combinational therapy not only effectively reversed the in vivo EMT process but also significantly lowered the collagen, creating favorable conditions for deep penetration of nanoparticles. More importantly, CFH/OM-L does not kill but inactivates CAFs, resulting in not only a low risk of tumor metastasis but also a reprogramming TME, such as M1 tumor-associated macrophages polarization and natural killer cells activation. Such strategy paves a moderate way to remold TME without depleting CAFs and provides a powerful tool to design strategies of combinational hepatocellular carcinoma therapy.