查找使用阿拉丁产品的科研文献

Harnessing synergistic SN38/quercetin nanomicelles via nebulized inhalation for enhanced lung cancer treatment

Fan Xudong,Luo Jingming,Tang XiaoQian,Zhang Jie,Zhang Ruoying,Cai Xinjun

Lung cancer remains a leading cause of cancer-related mortality worldwide, while the clinical utility of irinotecan-derived therapies is often constrained by poor drug solubility, suboptimal biodistribution, and systemic toxicity. To overcome these limitations, we developed polymeric nanomicelles co-loading 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan, and quercetin, a naturally occurring flavonoid with intrinsic antitumor activity, for nebulized inhalation delivery. The dual-drug nanomicelles (SN38/QU-PPM) were prepared by nanoprecipitation and exhibited a uniform particle size distribution, excellent stability, and pH-responsive drug release under acidic conditions. In vitro studies demonstrated that quercetin co-loading enhanced cellular uptake of the nanomicelles and promoted intracellular accumulation of SN38, resulting in significantly greater cytotoxicity against LLC-Luc lung cancer cells compared with SN38-loaded nanomicelles alone. In an orthotopic lung cancer model, nebulized inhalation of SN38/QU-PPM achieved a 3.33-fold higher pulmonary SN38 concentration than intravenous administration at 24 h. Nebulized SN38/QU-PPM also exhibited superior antitumor efficacy, achieving a tumor inhibition rate of 80.7%, accompanied by increased apoptosis, reduced tumor cell proliferation. Histopathological examination and serum biochemical analyses indicated no apparent treatment-related abnormalities following inhalation administration. Collectively, SN38/QU-PPM delivered via nebulized inhalation represents an effective lung-targeted drug delivery strategy that enhances local drug exposure and potentiates the antitumor efficacy of SN38. This dual-drug nanomicelle platform holds considerable promise for the treatment of lung cancer through nebulized inhalation therapy.

Empowering hydrophobic anticancer drugs by ultrashort peptides: General Co-assembly strategy for improved solubility, targeted efficacy, and clinical application

Feng Gao,Jun Guo,Shihao Liu,Feng Zhang,Yi Zhang,Liping Wang

The current state of drug delivery systems allows for the resolution of specific issues like inadequate solubility, limited targeting capabilities, and complex preparation processes, requiring tailored designs for different drugs. Yet, the major challenge in clinical application lies in surmounting these obstacles with a universal carrier that is effective for a variety of anticancer drugs. Herein, with the help of computer simulation, we rationally design ultrashort peptides GY and CCYRGD, which can co-assemble with hydrophobic anticancer drugs into nanoparticles with enhanced solubility, targeting ability and anticancer efficacy. Taking 7-ethyl-10-hydroxy camptothecin (SN38) as a model anticancer drug, the co-assembled SN38-GY-CCYRGD nanoparticles significantly enhance the water solubility of SN38 by more than three orders of magnitude. The as-prepared nanoparticles can effectively kill cancer cells, e.g., human small cell lung cancer (A549) cells with a notable cell mortality rate of 71%. Mice experimental results demonstrate the nanoparticles’ efficient targeting capability, marked reducing the toxicity to normal tissues while improving antitumor efficacy. This work presents a novel drug delivery method, integrating effective, targeted, and safe strategies into a comprehensive carrier system, designed for the administration of hydrophobic anticancer drugs.

Prodrug nanoparticles rationally integrating stroma modification and chemotherapy to treat metastatic pancreatic cancer

Liying Wang,Zimo Liu,Quan Zhou,Sufang Gu,Xiangsheng Liu,Jianxiang Huang,Haiping Jiang,Huifang Wang,Liping Cao,Jihong Sun,Youqing Shen,Huan Meng,Xiangrui Liu

Accumulating evidence suggests that stromal modifications improve chemotherapeutic outcomes in pancreatic ductal adenocarcinoma (PDAC). However, combination regimens of stroma-modifying agents and small-molecule cytotoxic drugs have achieved only limited improvements in the clinic, probably due to unsatisfactory pharmacokinetic profiles and restricted drug distribution in tumors. Here, we developed self-assembled prodrug nanoparticles integrating a stromal reprogramming inducer, calcipotriol (CAL), and a potent chemotherapeutic agent, 7-Ethyl-10-hydroxycamptothecin (SN38), to treat PDAC. While SN38 is conjugated to the block polymer backbone , CAL is loaded into the inner hydrophobic space during polymer self-assembly into nanoparticles. To achieve an efficient drug co-package, a planar and hydrophobic cholesterol domain was introduced to stabilize the hydrophobic CAL. Notably, the blood circulation time of CAL significantly improved as CAL|SN38 nanoparticle (CAL|SN38 NP). In addition, CAL|SN38 NP treatment significantly decreased the expression of N-cadherin, collagen , and fibronectin in tumors, which play critical roles in PDAC metastasis. Potent inhibition of primary tumor growth and vigorous anti-metastasis effects were observed after systemic administration of CAL|SN38 NP to stroma-rich PDAC orthotopic tumor-bearing mice. These findings provide a promising paradigm for developing tailor-made nanoparticles with potent stroma-modification capability to combat metastatic cancer.

A ROS-response hyaluronic acid-coated/chitosan polymer prodrug for enhanced tumour targeting efficacy of SN38

Jianpeng Qin,Meng Sun,Yanli Zhen,Ji Li,Dongkai Wang

Encapsulating GSH/NQO1-responsive SN38 prodrug micelles with Timosaponin AIII-based multifunctional liposomes for tumor-targeted chemotherapy

Xu Luo,Ziqiong Yang,Jianqiu Chen,Mengqi Shen,Kun Wang,Qian Du

Colorectal cancer chemotherapy faces challenges with low intratumoral drug accumulation and off-target toxicity. Micellar liposome complex carriers are a promising anti-cancer platform due to their high encapsulation efficiency, responsive release, and multi-targeting capabilities. This study explores a novel tumor-targeted chemotherapy approach by encapsulating GSH/NQO1-responsive SN38 prodrug micelles into cholesterol-replacement multifunctional liposomes. Timosaponin AIII (TAIII), a steroid saponin with anticancer activity, substitutes cholesterol to stabilize liposomes, benefiting from its steroidal aglycone structure. Additionally, TAIII mimics PEGylation via its glucose moiety, enhancing tumor targeting via the overexpression of glucose transporter 1 (GLUT1) on cancer cells. Molecular docking studies with AutoDock revealed that GLUT1 residues stabilize TAIII in the binding pocket through hydrogen bonding, hydrophobic, and polar interactions, promoting its transmembrane transport. A specific amphiphilic SN38 prodrug, PEG-SS-SN38-QPA (PSSQ), was synthesized and self-assembled into micelles via a solvent injection-dialysis method for GSH/NQO1-responsive controlled drug release in the tumor microenvironment. PSSQ micelles were integrated into the hydrophilic cavity of TAIII-based liposomes (TLP, prepared by the thin-film hydration method) through passive encapsulation to form PSSQ@TLP. In vitro release study exhibiting GSH/NQO1-triggered release under simulated tumor microenvironment. In vitro cytotoxicity evaluation was performed using the MTT assay on HCT116, LOVO, CT26.WT cell lines. Following in vivo evaluations of biodistribution, anti-tumor efficacy, and biosafety in CT26.WT xenograft tumor-bearing mice, PSSQ@TLP demonstrated enhanced intratumoral accumulation, robust tumor suppression, and minimized systemic toxicity, underscoring its promise as a targeted therapeutic strategy for colorectal cancer.

Delivery of a GPX4 Inhibitor by SN38 Prodrug Nanoassemblies for Amplified Antitumor Efficacy Based on Ferroptotic Chemotherapy

Lin Li,Yanyan Wu,Weiwei Wang,Kejing Wang,Lin Chen

Prodrug-based self-assembled nanoassemblies, with carrier-free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)-loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic-chemotherapy synergy. In this system, SN38 is conjugated to 1-octadecanol by a disulfide linkage to construct the self-assembly prodrug. DSPE-PEG 2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH-responsive release profile. Furthermore, ML210-loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy—using prodrug as “carriers” for ferroptosis inducers—offers a promising approach for synergistic antitumor therapy. Graphical Redox-responsive SN38-SS-1-octadecanol prodrug was synthesized and used as a “carrier” for ferroptosis activator (ML210). It is proven that ML210 can be successfully encapsulated loaded into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibited good stability and a GSH-responsive release profile. The co-assembled system of SN38 prodrug and ML210 can enhance antitumor efficiency by inducing multiple cell death pathway.

Hindering the unlimited proliferation of tumor cells synergizes with destroying tumor blood vessels for effective cancer treatment

Ya Liu,Yajun Xu,Ying Wang,Jianlin Lv,Kun Wang,Zhaohui Tang

The rational combination of chemotherapy drugs can improve the curative effect of cancer treatment. As two early recognized tumor hallmarks, the limitless replicative potential of tumor cells is essential for the development of their malignant growth state, and sustained angiogenesis is a prerequisite to the rapid growth of tumors. Based on this, we propose a combination therapy that hinders the unlimited proliferation of tumor cells and destroys tumor blood vessels. Herein, 7-ethyl-10-hydroxycamptothecin (SN38), a typical topoisomerase I inhibitor, was bonded to poly(L-glutamic acid) (PLG) to prepare the nanodrug SN38-NPs, which hinders the unlimited proliferation of tumor cells. A poly(L-glutamic acid)–combretastatin A4 conjugate (CA4-NPs), a representative vascular disrupting agent (VDA), was used to selectively disrupt the tumor blood vessels, cutting off the necessary nutrients and oxygen for the proliferation of tumor cells. In the 4T1 tumor model with an initial volume of about 400 mm3, the combined treatment of SN38-NPs and CA4-NPs showed an excellent cancer treatment effect with a tumor suppression rate of 94.3% and a synergistic interaction (Q = 1.25). Our study provides a new combination therapy approach for chemotherapy, with the hope of further improving the curative effect of anti-cancer therapy.

Novel disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate/human serum albumin nanoparticles for breast cancer therapy

Yanhao Zhang,Ji Wang,Chao Liu,Hanlei Xing,Yuhao Jiang,Xinsong Li

7-Ethyl-10-hydroxyl camptothecin (SN38), a semisynthetic derivative of camptothecin, exhibited extreme pharmacological activities in treating a range of cancers. However, its poor aqueous solubility and low stability hinder its clinical applications. Hence, a redox-responsive SN38 prodrug encapsulated human serum albumin (HSA) nanoparticle is developed to realize its potential in the clinic. First, a disulfide bond bridged 7-ethyl-10-hydroxyl camptothecin-undecanoic acid conjugate (SN38-SS-COOH) was synthesized and characterized structurally. After that, SN38-SS-COOH/HSA nanoparticles (SNH NPs) were prepared by the desolvation method. The SNH NPs with a feed molar ratio of 9 : 1 of SN38-SS-COOH : HSA showed a spherical structure with a diameter range of approximately 120–150 nm revealed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Fluorescence quenching confirmed the formation of SNH NP complexes by dual hydrophobic force and electrostatic interaction. The SNH NPs have a high drug loading of 10.44% and an encapsulation efficiency of 89.59% with good stability. Moreover, the redox responsiveness was validated by glutathione (GSH)-triggered accelerated release of parent drug SN38. In an in vivo pharmacokinetic study, the SNH NPs exhibited a significantly prolonged circulation time (t1/2, 3.77-fold) compared with free SN38. Finally, the in vivo antitumor efficacy and systemic toxicity of SNH NPs in a breast xenograft model were thoroughly evaluated. The inhibition rate of tumor growth induced by the SNH NPs reached 70.1%, while only 50.1% was achieved for irinotecan at an equivalent SN38 dosage of 10 mg kg−1. More importantly, the SNH NPs achieved a higher level of tumor growth inhibition (85.3%) by increasing the dosage to 60 mg kg−1 SN38 without obvious adverse effects. Taken together, the use of redox-responsive SN38 prodrug/HSA NPs could be a promising strategy to deliver highly active SN38 for breast cancer chemotherapy.

Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization

Li Guanting,Xia Fengli,Xiao Hongying,Zheng Shunzhe,Fu Shuwen,Qiao Han,Jin Qianhui,Zhang Xuanbo,Zhou Dun,Tian Chutong,Sun Jin,He Zhonggui,Sun Bingjun

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems. However, in the case of camptothecins-based prodrug nanoassemblies, linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies, which are highly unfavorable for sterilization through filtration, and may cause capillary blockage upon intravenous injection. The rational design of camptothecins-based prodrug nanoassemblies remains a challenge. Herein, we propose that branched aliphatic alcohol (BAA) functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies. Correspondingly, four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin (SN38) with BAAs of varying lengths via a tumor redox-responsive disulfide bond, which self-assemble into uniform spherical nanoparticles. The length of BAA was found to significant impact the multiple drug delivery process, including colloidal stability, drug release profiles and pharmacokinetics. Overall, SN38-C21 NPs (SN38-11-heneicosanol nanoparticles), featuring the longest BAA, showcased multiple therapeutic advantages, ultimately culminating the optimal antitumor efficacy and tolerance. The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies, and provide valuable insights for developing translational camptothecins-based nanomedicines.

A Polydopamine Nanoparticle-Knotted Poly(ethylene glycol) Hydrogel for On-Demand Drug Delivery and Chemo-photothermal Therapy

Xing Wang,Changping Wang,Xinyu Wang,Yitong Wang,Qiang Zhang,Yiyun Cheng

Hydrogels have exhibited remarkable benefits in drug delivery such as local delivery, days or even weeks of continuous drug release with improved bioavailability, and minimized adverse effects. Here we report a polydopamine (PDA) nanoparticle-knotted poly(ethylene glycol) (PEG) hydrogel for on-demand drug delivery and combined chemo-photothermal therapy. Anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN38) loaded on PDA nanoparticles via π–π interaction in the gel exhibit minimal leakage at physiological conditions and could be released in an on-demand fashion upon near-infrared light exposure. The hydrogel shows excellent biocompatibility and does not induce any foreign-body reaction over a four-month implantation. The in vivo results demonstrate that the PDA nanoparticle-knotted PEG hydrogel loaded with SN38 could efficiently suppress tumor growth by a combined chemo-photothermal therapy. This smart hydrogel would benefit a series of local treatments for diverse diseases.

Chemotherapeutics-enabled apoptosis-pyroptosis switch to trigger adaptive and innate immunity for metastatic breast cancer immunotherapy

Ying-Tao Zhong,Zi-Wen Qiu,Ke-Yan Zhang,Zhen-Ming Lu,Zhuo-Feng Li,Jun-Mei Nie,Yi Cen,Hong Cheng,Shi-Ying Li,Xiaoyuan Chen

Pyroptosis-inducing chemotherapeutics hold promise for activating both adaptive and innate immunity in breast cancer immunotherapy. However, their practical efficacy is often limited by inadequate expression of pyroptosis-executed gasdermin and insufficient transfer of tumor-derived DNA. In this work, our findings indicated that the epigenetic drug of decitabine (DEC) can increase the gasdermin E (GSDME) level in breast cancer cells, while the DNA-damaging chemotherapeutic drug of 7-ethyl-10-hydroxycamptothecin (SN38) can activate caspase-3 and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway. Based on these discoveries, a glutathione (GSH)-responsive nanoplatform equipped with PD-L1 blockade peptide (PD-L1 pep) is further fabricated for targeting delivery of these chemotherapeutic combination to breast cancer cells. Interestingly, the apoptosis-pyroptosis switch (denoted as PL@SD) not only enables the cascade activation of caspase-3 and GSDME to induce an apoptosis-pyroptosis transition, but also accelerates the release of tumor-derived DNA through the pore-formation to elicit the cGAS-STING activity. Concurrently, PL@SD elevates dendritic cell maturation, cytotoxic T lymphocyte infiltration, natural killer cell recruitment and long-term immunological memory effect to boost adaptive and innate immunity, thus synergistically suppressing primary breast cancer, distant lung metastases and tumor rechallenge. Overall, this study presents an elaborate strategy for apoptosis-pyroptosis transition and cGAS-STING activation, which might provide a new insight to expand the applications of the existing therapeutic drugs for tumor immunotherapy.

Hybrid nanoparticle–mediated simultaneous ROS scavenging and STING activation improve the antitumor immunity of in situ vaccines

Jianing Li,Tianze Wu,Weidong Wang,Yimin Gong,Mingzhu Lu,Mengmeng Zhang,Wanyue Lu,Yaming Zhou,Yannan Yang

In situ vaccine (ISV) is a versatile and personalized local immunotherapeutic strategy. However, the compromised viability and function of dendritic cells (DCs) in a tumor microenvironment (TME) largely limit the therapeutic efficacy. We designed a hybrid nanoparticle–based ISV, which accomplished superior cancer immunotherapy via simultaneously scavenging reactive oxygen species (ROS) and activating the stimulator of interferon genes (STING) pathway in DCs. This ISV was constructed by encapsulating a chemodrug, SN38, into diselenide bond–bridged organosilica nanoparticles, followed by coating with a Mn2+-based metal phenolic network. We show that this ISV can activate the STING pathway through Mn2+ and SN38 comediated signaling and simultaneously scavenge preexisting H2O2 in the TME and Mn2+-catalyzed •OH by leveraging the antioxidant property of diselenide and polyphenol. This ISV effectively activated DCs and protected them from oxidative damage, leading to remarkable downstream T cell activation and systemic antitumor immunity. This work highlights a nanoparticle design that manipulates DCs in the TME for improving the ISV.