Fundamental Research
·
2024
·
IF 5.7
Bowen Zhang,Wenyuan Liu,Jinrui Liu,Minglong Huang,Yaqiao Li,Erwei Zhao,Lurong Zhang,Xianbao Shi,Jin Sun,Zhonggui He,Lingxiao Li,Bingjun Sun
Mitoxantrone (MTO) is an anthraquinone antitumor drug with potent therapeutic benefits. However, its clinical application is restricted by the severe side effects stemming from poor tumor selectivity. In this study, MTO and cholesterol (CLS) were conjugated via a tumor-selective disulfide bond to obtain the MTO-SS-CLS prodrug. Interestingly, the MTO-SS-CLS could self-assemble into uniform nanoassemblies, and the addition of DSPE-PEG 2K significantly improved its self-assembly behavior and stability. Moreover, compared with MTO solutions, the disulfide bond-bridged MTO-SS-CLS nanoassemblies exhibited heightened tumor selectivity and pharmacokinetic properties. In addition, the prodrug nanoassemblies improved the tolerated dose and safety of MTO without compromising its therapeutic effect. This research enriches the pharmaceutical research of MTO and paves the way for its extensive clinical application.
研究领域:
药学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jiayu Guo,Xiaoxiao Zhang,Fudan Dong,Simeng Wang,Danping Wang,Yaqiao Li,Shiyi Zuo,Qing Wang,Wenxiao Li,Jin Sun,Zhonggui He,Tianhong Zhang,Qikun Jiang,Bingjun Sun
Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine ( GEM ) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.
研究领域:
药学
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 1
·262
·
IF 5.4
Yuting Liu,Xinhui Wang,Zhe Wang,Rui Liao,Qian Qiu,Yuequan Wang,Cong Luo
Cabazitaxel (CTX) has distinct therapeutic merits for advanced and metastatic cancer. However, the present clinical formulation (Jevtana®) has several defects, especially for undesirable tumor-targeting and serious side effects, greatly limiting the therapeutic efficacy. Small-molecule prodrug-based nanoassemblies integrate the advantages of both prodrug strategy and nanotechnology, emerging as a promising treatment modality. Herein, disulfide bonds with different lengths were employed as linkages to elaborately synthesize three redox-sensitive stearyl alcohol (SAT)-CTX prodrug-based nanoassemblies (SAC NPs, SBC NPs and SGC NPs) for seeking optimal chemotherapeutical treatment. All the prodrug-based nanoassemblies exhibited impressive drug-loading efficiency, superior self-assembly capability and excellent colloidal stability. Interestingly, the drug release behaviors of three prodrug-nanoassemblies in the same reductive environment were different owing to tiny changes in the carbon chain length of disulfide bonds, resulting in disparate cytotoxicity effects, pharmacokinetic outcomes and in vivo antitumor efficacies. Among them, SAC NPs displayed rapid drug release, excellent cytotoxicity, long blood circulation and enhanced tumor accumulation, thus showing strong tumor inhibition in the 4T1-bearing mouse model. Our study shed light on the vital role of connecting bonds in designing high-efficiency, low-toxicity prodrug nanoassemblies.Keywords:cabazitaxel;disulfide bond;prodrug nanoassemblies;reduction-responsive;cancer therapy
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Tian Liu,Fengli Xia,Yi Zheng,Hongying Xiao,Yuanhao Yu,Jianbin Shi,Shuo Wang,Xianbao Shi,Zhonggui He,Jin Sun,Bingjun Sun
The rational design of tumor-responsive prodrug nanoassemblies requires precise control over systemic stability and site-specific activation. While α-position disulfide bonds are advantageous for rapid response to redox conditions, they also risk premature drug leakage during circulation. This study introduces a steric hindrance-guided approach to engineer disulfide-bridged podophyllotoxin homodimeric prodrugs for spatiotemporal controlled delivery. By monomethyl or dimethyl substitution of the carbon atoms adjacent to the α-disulfide bond, we can modulate steric hindrance. Excessive hindrance destabilizes the nanoassemblies and slows effective drug release, while moderate hindrance (monomethyl modification) enhances pharmacokinetic properties and promotes selective tumor activation. In vivo studies indicate that monomethyl-modified prodrug nanoassemblies exhibit superior antitumor efficacy and reduced off-target toxicity compared to PPT solution. This work underscores the importance of steric hindrance in optimizing prodrug nanoassembly stability and tumor-specific activation, offering a comprehensive strategy for redox-responsive nanomedicines.
研究领域:
药剂学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Fei Wu,Chunxue Song,Hanxiao Yin,Ronglong Chen,Guanyu Huang,Jiajun Zhang,Haimin Chen,Li Lin,Junqiang Yin,Lisi Xie,Weihai Liu
Poor bioavailability and dose-limiting cardiotoxicity persistently hinder the clinical application of bufalin (BF). Conventional BF-based nanoagents have shown promise in tackling these challenges, yet advanced nanostrategies with further improved performance and clinical accessibility still await development. Herein, we introduce a novel cooperative nanoparadigm based on disulfide-linked bufalin homodimeric prodrugs (SBF) and metal phenolic networks (MPNs). This strategy achieves high drug-loading capacity and structural stability. Stability perturbation experiments reveal that hydrophobic interactions, electrostatic adsorption, and coordination bonds synergistically drive co-assembly of SBF and MPNs. The resultant nanopartieles (MSBNAs) exhibit prolonged circulation kinetics, tumor-selective accumulation, and pH/GSH dual-responsive properties, effectively mitigating BF-induced cardiotoxicity. Further antitumor mechanistic investigations unveil that MSBNAs amplify BF-induced ferroptosis through a dual assault of oxidative stress and iron overload induced jointly by MPNs-delivered exogenous iron and BF-triggered endogenous iron. This increased ferroptosis endows MSBNAs with superior suppression of tumor growth and lung metastasis, maintaining excellent biocompatibility without cardiotoxicity. Our work not only establishes a promising candidate platform to surmount the therapeutic hurdles of BF but also enriches the design landscapes of co-assembled nanomedicines, thereby laying a foundation for the clinical translation of BF and other antitumor drugs.
研究领域:
药学
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 6
·期 9
·2360-2374
·
IF 5.831
Dong Zhang,Jincheng Yang,Jibin Guan,Bin Yang,Shenwu Zhang,Mengchi Sun,Ruitao Yang,Tao Zhang,Ruoshi Zhang,Qiming Kan,Haotian Zhang,Zhonggui He,Lei Shang,Jin Sun
Prodrug self-nanoassemblies have many advantages for anticancer drug delivery, including high drug loading rate, resistance to recrystallization, and on-demand drug release. However, few studies have focused on their protein corona, which is inevitably formed after entering the blood and determines their subsequent fates in vivo. To actively tune the protein corona of prodrug nanoassemblies, three maleimide-paclitaxel prodrugs were synthesized via different redox-sensitive linkers (ester bond, thioether bond and disulfide bond). After incubation with rat plasma, the surface maleimide groups effectively captured albumins, resulting in albumin-enriched protein corona. The recruited albumin corona enabled enhanced tumor accumulation and facilitated cellular uptake, ensuring the high-efficiency delivery of nanoassemblies to tumor cells. Surprisingly, we found that the traditionally reduction-sensitive disulfide bond could also be triggered by reactive oxygen species (ROS). Such a redox dual-responsive drug release property of the disulfide bond-containing prodrug nanoassemblies further increased the selectivity in cytotoxicity between normal and tumor cells. Moreover, the disulfide bond-containing prodrug nanoassemblies exhibited the highest antitumor efficacy in vivo compared to marketed Abraxane® and other prodrug nanoassemblies. Thus, the fabrication of the maleimide-decorated disulfide bond bridged prodrug nanoassembly, integrating a tunable protein corona and on-demand drug release, is a promising strategy for improved cancer chemotherapy.
研究领域:
药学
·
生物医学工程
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2020
·Vol. 16
·期 45
·2005039
·
IF 11.459
Shiyi Zuo,Bingjun Sun,Yinxian Yang,Shuang Zhou,Yu Zhang,Mengran Guo,Mengchi Sun,Cong Luo,Zhonggui He,Jin Sun
The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off-target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond-bridged dimeric prodrug can self-assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self-assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox-sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor-specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in-depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency–low toxicity chemotherapeutical nanomedicines.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Tao Sheng,Shuai Xia,Jia-Min Li,Ruo-bin Peng,Pingbo Yan,Bing-Feng Zhang
The activation and inflammation of hepatic stellate cells (HSCs) promoted the progression of liver fibrosis. The antioxidant and anti-inflammatory therapy can effectively alleviate liver fibrosis. Here, dual prodrug nanoassemblies modified with chitosan (CS/HS-HD NPs) was constructed. The particle size of CS/HS-HD NPs was about 200 nm, which was uniformly dispersed spherical particles, and Zeta potential was positive. The CS/HS-HD NP loaded SLB 3.66 ± 0.04 % and DEX 0.52 ± 0.01 %. In vitro stability and release investigation showed CS/HS-HD NPs had good stability and sustained release characteristics without burst release. These results of in vivo pharmacokinetics, intestinal absorption and in vivo distribution showed that CS/HS-HD NPs had longer t l/2 and larger AUC than other groups (Free drug, HS-HD NPs), which significantly enhanced intestinal absorption and specific accumulation in the liver. In CCl 4 -induced liver fibrosis, CS/HS-HD NPs significantly inhibited the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-12, and increased anti-inflammatory cytokines IL-10 level, and then reduce the infiltration of inflammatory cells. The image of liver, HE staining, Masson staining showed CS/HS-HD NPs reduced collagen deposition and liver pathological damage, effectively improved liver fibrosis. Taken together, these findings suggested chitosan coated hybrid prodrug-nanoassemblies could adjust inflammatory cytokines and improve therapeutic effect on liver fibrosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Hezhen Xu,Shiyi Zuo,Danping Wang,Yu Zhang,Wenxiao Li,Lingxiao Li,Tian Liu,Yuanhao Yu,Qingzhi Lv,Zhonggui He,Jin Sun,Bingjun Sun
The clinical application of cabazitaxel (CTX) is restricted by severe dose-related toxicity, failing to considering therapeutic efficacy and safety together. Self-assembled prodrugs promote new drug delivery paradigms as they can self-deliver and self-formulate. However, the current studies mainly focused on the use of straight chains to construct self-assembled prodrugs, and the role of branched chains in prodrug nanoassemblies remains to be clarified. In this study, we systematically explored the structure–function relationship of prodrug nanoassemblies using four CTX prodrugs that contained branched chain aliphatic alcohols (BAs) with different alkyl lengths. Overall, CTX-SS-BA 20 NPs with the proper alkyl length exhibited significant improvements in both antitumor efficacy and biosafety. Furthermore, compared with straight chain (SC) modified prodrug nanoassemblies (CTX-SS-SC 20 NPs), CTX-SS-BA 20 NPs still hold great therapeutic promise due to its good biosafety. These findings illustrated the significance of BAs as modified chains in designing prodrug nanoassemblies for narrowing the efficacy-to-safety gap of cancer therapy.
研究领域:
药学
·
纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2023
·
IF 9.9
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.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2023
·
IF 14.5
Shuo Wang,Tian Liu,Yuetong Huang,Chaoying Du,Danping Wang,Xiyan Wang,Qingzhi Lv,Zhonggui He,Yinglei Zhai,Bingjun Sun,Jin Sun
The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C 16 , C 18 , C 20 , and C 24 ). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules’ sensitivity. The extension of the carbon chains improved the prodrugs’ self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C 20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.
研究领域:
药学
·
纳米技术
·
药物递送系统
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2019
·Vol. 10
·期 1
·1-10
·
IF 11.878
Sun Bingjun,Luo Cong,Zhang Xuanbo,Guo Mengran,Sun Mengchi,Yu Han,Chen Qin,Yang Wenqian,Wang Menglin,Zuo Shiyi,Chen Pengyu,Kan Qiming,Zhang Haotian,Wang Yongjun,He Zhonggui,Sun Jin
Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
·
氧化还原生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）