Engineering nanomedicines for immunogenic eradication of cancer cells:Recent trends and synergistic approaches

Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies including chemotherapy,radiotherapy,photodynamic,photothermal,magnetic,chemodynamic,sonodynamic and oncolytic therapy,have been developed to induce immunogenic cell death(ICD)of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response.However,many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response.Here,we outline the current state of using nanomedicines for boosting ICD of cancer cells.Moreover,synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints,phagocytosis,macrophage polarization,tumor hypoxia,autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed.We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses.Endoplasmic reticulum localized ICD,focused ultrasound hyperthermia,cell membrane camouflaged nanomedicines,amplified reactive oxygen species(ROS)generation,metallo-immunotherapy,ion modulators and engineered bacteria are among the most innovative approaches.Various challenges,merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.

Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers

The complex physiological and pathological conditions form barriers against efficient drug delivery.Cell penetrating peptides(CPPs),a class of short peptides which translocate drugs across cell membranes with various mechanisms,provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers.After years of development,the function of CPPs is beyond cell penetrating.Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor,myocardial ischemia,ocular posterior segment disorders,etc.In this review,we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology,ophtalmology,mucus,neurology and cancer,etc.We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.

Nanomedicine strategies for sustained,controlled,and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells(CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability.They have been identified in a variety of tumors,including tumors of the digestive system.CSCs exhibit some unique characteristics,which are responsible for cancer metastasis and recurrence.Consequently,the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy.Several potential approaches to target CSCs of the digestive system have been explored,including targeting CSC surface markers and signaling pathways,inducing the differentiation of CSCs,altering the tumor microenvironment or niche,and inhibiting ATP-driven efflux transporters.However,conventional therapies may not successfully eradicate CSCs owing to various problems,including poor solubility,stability,rapid clearance,poor cellular uptake,and unacceptable cytotoxicity.Nanomedicine strategies,which include drug,gene,targeted,and combinational delivery,could solve these problems and significantly improve the therapeutic index.This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.

In Vivo Animal Model Evaluation of a Powerful Oral Nanomedicine for Treating Breast Cancer in BALB/c Mice Using 4T1 Cell Lines without Chemotherapy

Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nanopolymer as co-assistants coordinating with efficacious suitable wetting agents, PEG-binding compound, and W/O emulsifier for producing eco-friendly water-based nanodrug. Several characterization techniques containing SEM, TEM, FTIR, photoluminescence, zeta potential, and UV-Vis absorption were employed for ZnO Q-Dot NPs in nanodrug. This work aims to investigate the anti-tumor effects of such nanomedicine on the 4T1 breast cancer cell line in BALB/c mice, being elaborated through intraperitoneal, injection (IVP) and oral therapy. The impressive findings showed that ZnO nanodrug caused changes in blood factors, having the most effectiveness at 40 μg/ml concentration after two weeks of oral treatments. The significant increase in white blood cells (WBC) neutrophils and meaningful decreases in lymphocytes and especially cholesterol were powerful simultaneous impacts, successfully treating malignant breast cancer masses. In this significant animal model research for breast cancer, the sick mice recovered entirely and even had a safe space to mate. Histopathological results showed no evidence of breast tumor formation or metastasis in the group treated with nanodrug and their children. This nanomedicine has a therapeutic effect, and is ready to be applied for treating volunteer breast cancer patients. However, its prevention (inhibitory) effect can also be analyzed and added to current data in future studies.

靶向纳米药物在胶质瘤治疗中的研究进展

胶质瘤为源于星形胶质细胞中枢神经系统的多发性恶性肿瘤,常规化学治疗效果不佳。纳米药物易穿越血脑屏障、高效阻断胶质瘤干细胞增殖分化和侵袭、激活肿瘤免疫、干扰肿瘤代谢过程、沉默肿瘤基因、多功能载药阻断肿瘤增殖相关信号系统等,有效遏制胶质瘤各种恶性生物学行为,在胶质瘤治疗中凸显优势。本文对靶向纳米药物在胶质瘤治疗中的应用研究进展进行综述,为纳米药物在胶质瘤治疗中的应用提供理论依据。

Nanomedicine-mediated immunogenic cell death and its combination with immune checkpoint blockade therapy

Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade(ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment(TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death(ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.

Advancements in precision nanomedicine design targeting the anoikis-platelet interface of circulating tumor cells

Tumor metastasis,the apex of cancer progression,poses a formidable challenge in therapeutic endeavors.Circulating tumor cells(CTCs),resilient entities originating from primary tumors or their metastases,significantly contribute to this process by demonstrating remarkable adaptability.They survive shear stress,resist anoikis,evade immune surveillance,and thwart chemotherapy.This comprehensive review aims to elucidate the intricate landscape of CTC formation,metastatic mechanisms,and the myriad factors influencing their behavior.Integral signaling pathways,such as integrin-related signaling,cellular autophagy,epithelial-mesenchymal transition,and interactions with platelets,are examined in detail.Furthermore,we explore the realm of precision nanomedicine design,with a specific emphasis on the anoikis‒platelet interface.This innovative approach strategically targets CTC survival mechanisms,offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy.The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.

心血管纳米医学在血管平滑肌细胞中的应用

血管平滑肌细胞(vascular smooth muscle cell, VSMC)具有调节血管紧张性和维持血管形态的功能,其功能障碍与心血管疾病的发生、发展密切相关。纳米医学(nanomedicine)是指纳米材料在医学中的应用,因其能够克服传统治疗方式存在的药理学局限,如药物选择性差、生物利用度低等问题,被广泛应用于心血管疾病、肿瘤等的诊断和治疗。本文基于VSMC在心血管系统的关键作用和纳米医学在传统给药系统中的优化作用,概述了VSMC表型转换异常、恶性增殖和迁移引发心血管疾病的病理机制,总结了靶向改善VSMC功能来治疗心血管疾病的纳米应用,如靶向药物递送、自身靶向干预和组织工程支架制备等,最后讨论了心血管纳米医学面临的挑战和未来发展的方向,以期为预防和治疗心血管疾病提供潜在方案。

双模态成像仿生纳米粒对甲状腺髓样癌的声动力治疗

背景:声动力疗法作为一种新型抗肿瘤治疗手段具有非侵入性和时空可控性的特点,在甲状腺髓样癌无创性治疗中具有广阔的应用前景。目的:制备具有双模态成像能力的仿生癌细胞膜涂层脂质纳米粒,检测纳米粒的理化性质、靶向能力、成像效果、细胞毒性和抗迁移能力。方法:以二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000、胆固醇、血卟啉单甲醚、全氟己烷为原料,通过薄膜水合-超声振荡法制备脂质纳米粒HP@LNP,其中血卟啉单甲醚装载于脂质纳米结构的疏水层,全氟己烷装载于脂质纳米结构的亲水核心层内;将甲状腺髓样癌细胞膜包覆于脂质纳米粒HP@LNP表面,构建具有主动靶向甲状腺髓样癌细胞能力的仿生脂质纳米粒MHP@LNP。表征纳米粒MHP@LNP的理化性质、靶向能力、免疫逃逸能力、成像效果、细胞毒性和抗迁移能力。结果与结论:①脂质纳米粒MHP@LNP呈现典型的核壳结构,粒径为131.06 nm,平均电位为-30.59 mV,凝胶电泳结果显示脂质纳米粒MHP@LNP与癌细胞膜蛋白图谱相符合,荧光共定位结果显示脂质纳米粒MHP@LNP与癌细胞膜的荧光信号显著重合。脂质纳米粒MHP@LNP纳米粒内血卟啉单甲醚的包封率为87.8%,载药率为14.6%。在低强度聚焦超声刺激下,脂质纳米粒MHP@LNP可发生相变产生微泡,在4 min时超声信号强度达到最大值。在激光照射下,脂质纳米粒MHP@LNP的光声信号强度与其质量浓度呈现线性相关。脂质纳米粒MHP@LNP具有同源细胞靶向能力和免疫逃逸能力。未经低强度聚焦超声照射前的脂质纳米粒MHP@LNP具有良好的生物相容性,而经低强度聚焦超声照射后产生具有细胞毒性的活性氧,有效杀伤甲状腺髓样癌细胞,并抑制甲状腺髓样癌细胞的迁移能力。②结果表明,脂质纳米粒MHP@LNP能够在超声和光声双模态成像引导下实现声动力治疗,用于治疗甲状腺髓样癌。

Echographic imaging of tumoral cells through novel nanosystems for image diagnosis

Since the recognition of disease molecular basis,it has become clear that the keystone moments of medical practice,namely early diagnosis,appropriate therapeutic treatment and patient follow-up,must be approached at a molecular level.These objectives will be in the near future more effectively achievable thanks to the impressive developments in nanotechnologies and their applications to the biomedical field,starting-up the nanomedicine era.The continuous advances in the development of biocompatible smart nanomaterials,in particular,will be crucial in several aspects of medicine.In fact,the possibility of manufacturing nanoparticle contrast agents that can be selectively targeted to specific pathological cells has extended molecular im-aging applications to non-ionizing techniques and,at the same time,has made reachable the perspective of combining highly accurate diagnoses and personalized therapies in a single theranostic intervention.Main developing applications of nanosized theranostic agents include targeted molecular imaging,controlled drug release,therapeutic monitoring,guidance of radiationbased treatments and surgical interventions.Here we will review the most recent findings in nanoparticles contrast agents and their applications in the field of cancer molecular imaging employing non-ionizing techniques and disease-specific contrast agents,with special focus on recent findings on those nanomaterials particularly promising for ultrasound molecular imaging and simultaneous treatment of cancer.

Green Synthesis and Characterization of Gold Nanoparticles: Study of Its Biological Mechanism in Human SUDHL-4 Cell Line

In this investigation, the anticancer potentiality and biological mechanism of gold nanoparticles (AuNPs) was studied in SUDHL-4 cell line. Metallic AuNPs were prepared and stabilized with ethanol clove (Syzygium aromaticum) extract. The green synthesis of AuNPs was characterized and evaluated by UV-Visible Spectroscopic, X-ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Transmission electron microscopy (TEM), Dynamic Light Scattering (DLS) and biological activities using various biochemical assays. Green synthesis of AuNPs was confirmed by instrument method. The TEM images show polydis-perse, mostly spherical AuNPs particles of 12 - 20 nm. AuNPs were decreased the growth and viability of SU-DHL-4 cell line and increased the apoptosis. The treatments of SU-DHL-4 cells with AuNPs resulted in a moderate considerably increase in Reactive oxygen species (ROS) production. We measured apoptosis by Annexin-V/propidium iodide (PI) in the existence and nonexistence of the antioxidant N-acetyl-L-cysteine (NAC), the glutathione-depleting agent buthionine sulfoximine (BSO), or caspase inhibitors to determine the mechanism of cell death. AuNPs are unique potential anticancer agents that cause ROS-dependent apoptosis in SUDHL-4 cell line which was improved by depletion of glutathione (GHS) and inhibited by N-acetyl-L-cysteine on Z-VAD-FMK.

Nanomedicine approaches for treatment of hematologic and oncologic malignancies

Cancer is a leading cause of death worldwide.Nowadays,the therapies are inadequate and spur demand for improved technologies.Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality.Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs,thereby reducing their toxicity.Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer.Immunotherapy is revolutionizing cancer treatment,as it can achieve unprecedented responses in advanced-stage patients,including complete cures and long-term survival.A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities(as in the case of the nanodrug Ferumoxytol).Furthermore,the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside.The most common example includes lipidbased nanoparticles that target VEGF-Αand KRAS pathways.This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies.The insights provided and the evidence obtained in this paper indicate a bright future ahead for immunooncology applications of engineering nanomedicines.

干细胞来源外泌体miRNA介导心脏修复的研究进展

在过去几十年中,急性心肌梗死采用开通罪犯冠状动脉和血运重建术等新技术已经显著改善了心肌梗死的预后,但仍有许多患者心肌梗死后出现不良的心脏重构及心力衰竭。随着心力衰竭的流行,急需一种新的治疗方法,无细胞疗法是一种很有前途的治疗方法,在多种急慢性心脏病中调节并促进心脏修复。现就干细胞来源外泌体微RNA在心肌损伤后介导心脏修复的研究进展进行综述。

Macrophage membrane-coated nanovesicles for dual-targeted drug delivery to inhibit tumor and induce macrophage polarization

Background:Immunosuppressive M2 macrophages in the tumor microenvironment(TME)can mediate the therapeutic resistance of tumors,and seriously affect the clinical efficacy and prognosis of tumor patients.This study aims to develop a novel drug delivery system for dual-targeting tumor and macrophages to inhibit tumor and induce macrophage polarization.Methods:The anti-tumor effects of methyltransferase like 14(METTL14)were investigated both in vitro and in vivo.The underlying mechanisms of METTL14 regulating macrophages were also explored in this study.We further constructed the cyclic(Arg-Gly-Asp)(cRGD)peptide modified macrophage membrane-coated nanovesicles to co-deliver METTL14 and the TLR4 agonist.Results:We found that METTL14 significantly inhibits the growth of tumor in vitro.METTL14 might downregulate TICAM2 and inhibit the Toll-like receptor 4(TLR4)pathway of macrophages,meanwhile,the combination of METTL14 and the TLR4 agonist could induce M1 polarization of macrophages.Macrophage membrane-coated nanovesicles are characterized by easy modification,drug loading,and dual-targeting tumor and macrophages,and cRGD modification can further enhance its targeting ability.It showed that the nanovesicles could improve the in vivo stability of METTL14,and dual-target tumor and macrophages to inhibit tumor and induce M1 polarization of macrophages.Conclusions:This study anticipates achieving the dual purposes of tumor inhibition and macrophage polarization,and providing a new therapeutic strategy for tumors.

Modularly designed peptide-based nanomedicine inhibits angiogenesis to enhance chemotherapy for post-surgical recurrence of esophageal squamous cell carcinomas

Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgical resection promotes the local angiogenesis at the tumor site,further exacerbating the proliferation and invasion of residual tumor cells,it is urgent to inhibit angiogenesis after surgery.Here,a functional peptide-based nanomedicine was obtained from peptide–drug conjugates,which are composed of a hydrophilic targeting motif(vascular endothelial growth factor family and their receptors(VEGFR)targeting peptide for anti-angiogenesis),an ester-linked hydrophobic oridonin(ORI).The nanomedicine exhibits esterase-catalyzed disassembly and drug release,significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies.This study provides an integrated solution for anti-angiogenesisaugmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.

基于3D细胞培养模型的新型纳米载药系统抗胆囊癌活性的效果及作用机制

目的通过建立胆囊癌3D细胞培养模型,研究新型纳米载药系统对胆囊癌细胞的杀伤效果及作用机制。方法构建胆囊癌细胞GBC-SD的2D/3D培养模型,利用MTT、HE染色、流式细胞仪(FCM)、Hoechst/PI凋亡检测等方法探索叶酸修饰的聚己内酯基药物P(CL-co-OPD)纳米载药系统CP24对正常细胞的毒性以及载药后对胆囊癌细胞的抑制率计量资料比较采用t检验。结果 HE染色显示纳米载药系统CP24对肝肾细胞未见明显细胞毒性。FCM法显示CP24对胆囊癌细胞无明显杀伤作用。在氟尿嘧啶(5-Fu)浓度为100μg/ml时,5-Fu-CP24组以及单纯5-Fu组在3D细胞模型下对肿瘤的杀伤和抑制效果均较2D细胞模型下减低。无论在2D/3D细胞模型下,5-Fu-CP24组对肿瘤细胞的杀伤效果均显著强于单纯5-Fu组(P<0.05),通过Hoechst/PI凋亡检测前者引起细胞的死亡以凋亡为主,后者以坏死为主。结论 3D细胞培养可以更加真实的反映体内细胞之间的微环境,细胞间基质的影响可能使细胞对药物的敏感性降低。携5-Fu的纳米载体比原药5-Fu能引起更多的细胞死亡,这种可降解纳米载药系统具有良好的载药性、缓释性及生物安全性,其对于胆囊癌的化疗具有广阔的应用前景。

纳米药物在肺癌治疗中的研究进展

近年来纳米技术在肿瘤检测、诊断及治疗的发展与应用方面取得了巨大的进步,最终形成"肿瘤纳米药物"的新兴领域。纳米颗粒因能克服生理屏障、有效地输送疏水性药物,并特异性地靶向到肿瘤组织中而倍受关注。目前,纳米药物主要包括脂质纳米粒、聚合物纳米粒、金纳米粒、磁纳米粒、介孔二氧化硅等不同剂型。以纳米材料为载体在肺癌的治疗有独特的优势,在实现靶向性给药、缓释药物、提高难溶性药物与多肽药物的生物利用度、降低药物的不良反应等方面表现出明显的优势,具有广阔的研究和开发前景。

纳米粒子在靶向肿瘤干细胞治疗癌症中的应用

肿瘤干细胞具有自我更新能力,持续增殖潜能,是肿瘤耐药性、肿瘤复发迁移的根本原因。此外,肿瘤干细胞对于传统的化疗、放疗具有耐受性。因此,有效的清除肿瘤干细胞是治疗癌症的关键。纳米载体可以增强药物的溶解度和生物安全性,延长循环时间,且纳米材料可以应用于热疗等疗法中。目前,应用纳米药物靶向肿瘤干细胞在癌症治疗方面取得了诸多进展。本文介绍了靶向肿瘤干细胞的纳米粒子在化疗、基因治疗、热疗方面的应用研究,指出多疗法、多靶向的联合治疗是提高纳米粒子治疗肿瘤的有效途径,诊疗一体化的纳米粒子是未来治疗癌症的发展趋势。

口腔鳞癌叶酸表达的临床病理分析

目的:观察口腔鳞状细胞癌(OSCC)中叶酸受体(FRα)的表达水平及其与肿瘤临床病理的关系。方法:免疫组化方法分析95例OSCC患者FRα表达情况,分析其与临床参数、总生存率(OS)和无病生存率(DFS)的相关性。结果:95例OSCC组织FRα中、高表达占57.9%。5年OS,FRα高、中、低表达者分别为33.4%、79.4%、90.1%(P=0.0003);5年DFS在FRα高、中、低表达患者中分别为44.7%、82.9%、69.5%(P=0.0336)。FRα表达与OSCC的肿瘤浸润方式、淋巴结转移、肿瘤分期密切相关,FRα高表达与OS和DFS负相关(P<0.05)。结论:FRα表达与OSCC临床病理进展相关。

仿生型纳米红细胞靶向药物递送系统的制备及体内外抗肿瘤效果评价

目的构建精氨酸-甘氨酸-天冬氨酸(RGD)修饰的包载阿霉素(DOX)的仿生型纳米红细胞(NE)靶向药物递送系统RGD-NE-DOX,并进行体内外抗肿瘤效果评价。方法通过物理挤压法制备包载DOX的纳米红细胞NE-DOX,RGD修饰后构建RGD-NE-DOX,检测其形态、粒径、电位、载药量和包封率,透析法测定体外释药特性,共聚焦显微镜观察体外摄取情况及靶向性,并进行体内组织分布及药效学研究。结果制备的RGD-NE-DOX呈球形,平均粒径(197.41±2.27) nm,聚合物分散性指数(PDI)为(0.21±0.02),电位(-16.87±1.51) mV,载药量(14.8±1.2)%,包封率(58.69±3.7)%;RGD-NE-DOX较单纯DOX突释降低,缓释特性明显;乳腺癌细胞MCF-7对RGD-NE-DOX的摄取多于NE-DOX和游离DOX,但正常乳腺细胞Hs578Bst几乎不摄取RGD-NE-DOX;体内组织分布结果表明RGD-NE-DOX肿瘤靶向性强,作用时间长;药效学结果表明RGD-NE-DOX抗肿瘤作用更强(P<0.05),组织切片显示具有良好生物相容性。结论仿生型纳米药物递送系统RGD-NE-DOX循环时间长,具有良好的生物相容性及靶向性,抗肿瘤效果明显,具有广阔的应用前景。