JOURNAL OF SUPERCRITICAL FLUIDS
·
2017
·
IF 2.991
Biao-Qi Chen,Ranjith Kumar Kankala,Shi-Bin Wang,Ai-Zheng Chen
Despite the significant advancements in the pharmaceutical manufacturing process, the aqueous solubility of most of the potent drugs has remained as an unresolved problem during the formulation development and drug delivery processes. To address this critical issue, we modified the continuous-rapid expansion of supercritical solution (RESS-C) process, which is incessant, stable and well-regulated. Initially, the solubility of lonidamine (LND) in supercritical carbon dioxide (SC-CO 2 ) was tested using a static analytical method at altered critical conditions ( T : 308.15-328.15 K, P : 10.0-30.0 MPa). Under optimized conditions (LND conc.- 0.5% (w/v), flow rate- 1.0 mL/min, T - 328.15 K, P - 20.0 MPa and CO 2 flow rate- 30.0 g/min), the modified RESS-C process resulted in nano-sized spheres with a smooth surface and a narrow particle size distribution. Further, the crystal properties of the samples and their molecular interactions were elucidated. The altered physical state of RESS-C processed LND from crystalline to amorphous resulted in the solubility improvement and also enhanced the in vitro antiproliferative effects compared to the unprocessed LND, demonstrating the potential of the modified RESS-C process in improving the bioavailability of poorly water-soluble drugs.
研究领域:
药剂学
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制药工程
·
药物递送
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产品关联
DOI
高影响因子
Gels
·
2026
·Vol. 12
·期 8
·682
·
IF 6.4
Li Fan,Yuhan Sun,Guangzhao Lu,Lijia Kong,Yangyuyuan Song,Rongrong Yu,He Zhang,Wei Wu,Huan Wang,Ying Lu
The high recurrence rate of glioblastoma after surgical resection and conventional chemotherapy remains a major obstacle to effective treatment. Mitochondria-targeted long-acting local chemotherapy represents a promising therapeutic strategy to tackle this dilemma. In this study, a mitochondria-penetrating peptide (mito) was conjugated with lonidamine (LND), a mitochondrial hexokinase II inhibitor, to construct an amphiphilic peptide–drug conjugate (LND-mito) that could self-assemble into supramolecular hydrogels. This design achieves sustained localized release and mitochondria-targeted delivery, generating a tumor-selective oxidative phosphorylation inhibitor with 19-fold higher potency than LND. Our results demonstrated that LND-mito efficiently targeted tumor cell mitochondria, induced robust reactive oxygen species generation, decreased mitochondrial membrane potential, and activated mitochondrial apoptosis, ultimately markedly inhibiting glioma growth and prolonging postoperative survival in orthotopic glioma-bearing mice. Collectively, this study offers a promising therapeutic strategy for glioma management, while simultaneously informing the design of high-efficacy, low-toxicity local sustained-release delivery platforms for malignant tumors.
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产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 42
·2104418
·
IF 18.808
Can Wu,Chunlu Wang,Yaoyao Zheng,Yaxin Zheng,Ziqi Liu,Keming Xu,Wenying Zhong
Cancerous cells exhibit overexpression of multiple enzymes in various cellular compartments. These enzymes are often undruggable, yet display unique advantages in regulating intracellular self-assembly and dis-assembly of small molecules for cancer targeting. Herein, a self-assembling molecule (LND-1p-ES) for carrier-free delivery of lonidamine specifically to cancerous cells is designed, where LND-1p-ES executes as both a drug and a carrier with combined benefits thereof. Under the precise regulation of phosphatase (ALP) and esterase (CES), LND-1p-ES is capable of self-assembling intracellularly in a spatiotemporal manner, to confer lonidamine-borne nanofibers with enhanced cellular uptake. These nanofibers also facilitate controlled drug release with the aid of cellular proteases. Taking advantages of overexpressing ALP and CES as well as proteases in cancerous cells, the LND-1p-ES formulation demonstrates enhanced potency and selectivity against melanoma cells A375 in vitro and in vivo. In comparison, none/single enzyme responsive compounds fail to show a similar potency or selectivity, further confirming the indispensable roles of these enzymes in the delivery system. Collectively, the research provides a viable strategy to utilize multiple enzymes in cancerous cells for regulation of intracellular self-assembly, which can be expanded to design smart soft materials responsive to multiple biologically relevant biomolecules for enhanced therapeutic efficacy.
研究领域:
癌症研究
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药物递送系统
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生物医学工程
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材料科学
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药学
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Can Wu,Qishu Jiao,Chunlu Wang,Yaxin Zheng,Xiaohui Pan,Wenying Zhong,Keming Xu
The use of lonidamine (LND) in photodynamic therapy (PDT) provides a viable approach to develop low-dose PDT modules with high efficacy, for LND potentiates cytotoxicity of photosensitizers through dysregulation of mitochondrial function. Yet, the efficacy of LND is restricted by its low accumulation in cancer cells, especially in the mitochondrial compartments. To address the problem, we design an LND-derived self-assembling peptide molecule (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. The targeted cellular delivery of LND-K gives higher efficacy in ablation of mitochondrial function in melanoma cells A375, as compared to free LND or the control molecule that lacks mitochondria-targeting moieties. To integrate LND-K in a typical PDT module, we develop a nanofibrillar hydrogel system through co-assembly of LND-K and TPPS 4 , an anionic photosensitizer that forms tight electrostatic interactions with cationic residues of LND-K. Notably, hydrogel formulation of LND-K/TPPS 4 facilitates slow release of TPPS 4 over 14 days in vitro , and displays a longer retention time than aqueous solution of TPPS 4 in vivo . By integrating a mitochondria-targeted molecule (LND-K) in a typical PDT module, we achieve synergistic killing of A375 cells with dual drugs, where LND-K not only serves as a chemotherapeutic drug, but also potentiates the cytotoxicities of TPPS 4 toward A375 cells in vitro and in vivo . The peptide-based drug self-delivery system promises the development of efficacious combination treatments against cancer, that integrate cell sensitization with existing anticancer modules ( e.g. , chemotherapy and PDT) for enhanced therapeutic efficacy. Statement of significance This study reports the design and synthesis of a lonidamine (LND)-derived self-assembling peptide (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. Under the precision guidance of a mitochondria-targeting sequence, LND-K-containing nanofibers target mitochondria and ablate mitochondrial functions. On one hand, the targeted delivery of LND-K reduces cell viabilities through a chemotherapy route; on the other hand, LND-K sensitizes cancer cells for subsequent PDT treatment with enhanced efficacy, which is mediated by induction of ROS, loss of mitochondrial membrane potential , and decrease of cellular ATP level. We believe that the design of mitochondria-targeted drug delivery systems with a self-assembling molecule provides a new approach to potentiate cytotoxicity of photosensitizers in a low-dose PDT module.
研究领域:
癌症治疗
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药学
·
生物技术
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材料科学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2015
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IF 8.557
Bing-Feng Zhang,Lei Xing,Peng-Fei Cui,Feng-Zhen Wang,Rong-Lin Xie,Jia-Liang Zhang,Mei Zhang,Yu-Jing He,Jin-Yuan Lyu,Jian-Bin Qiao,Bao-An Chen,Hu-Lin Jiang
The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan- graft -PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy.
研究领域:
药理学
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纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 7.088
Yi Zhao,Yao Peng,Zhongzhen Yang,Jiaqi Lu,Ru Li,Yuesen Shi,Yaxin Du,Ze Zhao,Li Hai,Yong Wu
To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis , inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis , and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.
研究领域:
药剂学
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肿瘤学
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纳米技术
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
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2022
·
IF 2.712
Lu Yang,Junnan Li,Zhaoyuan Guan,Jingwen Zhang,Xin Wang,Rupei Tang
Herein, we combined a derivative of cisplatin (CP) and the chemosensitizer lonidamine (LND) to design an amphiphilic prodrug, in which the ratio of LND to cisplatin was fixed at 2:1. Diaminedichlorodihydroxyplatinum (DH-CP) is a hydrophilic cisplatin derivative. Due to its appropriate amphiphilicity, this prodrug could self-assemble into stable nanoparticles (denoted as LNP-NPs). Under the action of excessive glutathione (GSH) in tumor cells, DH-CP could be reduced to cytotoxic cisplatin. In addition, the released LND could inhibit the metabolic process of tumor cells, and improving the sensitivity of tumor cells to cisplatin. In vitro studies demonstrated that LNP-NPs displayed significantly cytotoxicity on breast cancer cells, and the cell viability after co-incubation for 48 h (CP 16 μg/mL) were 18.77% (MCF-7) and 20.01% (EMT6), respectively. LNP-NPs could also significantly inhibit the growth of MCF-7 tumor-like spheroids, which were realized through the high coordination and cooperation between CP and LND. Therefore, the carrier-free drug delivery system based on LND and DH-CP is expected to achieve a good synergistic anti-tumor effect.
研究领域:
药学
·
肿瘤学
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纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2025
·
IF 2.5
Yimei Zhang,Chen Yuan,Wenwen Yang,Dianyong Tang,Zhongzhu Chen,Zheng Huang
Multidrug resistance, in particular the challenge of drug efflux transporter-mediated chemoresistance, remains the major obstacle for effective chemotherapy. Therefore, manipulating energy metabolism in cancer cells to reduce the expression of P-glycoprotein (P-gp) and disrupt redox homeostasis may be a potential strategy to surmount cancer therapeutic resistance. Herein, a PEGylated co-delivery nanoplatform (LND-DOX NPs) that is capable of decreasing chemotherapeutic drug efflux and increasing the sensitivity of tumor cells to DOX by manipulating energy metabolism and disrupting redox homeostasis is rationally designed. As a result, the LND-DOX NPs increased DOX retention in MCF-7/Adr cells and displayed remarkable antitumor capabilities. The IC50 value of LND-DOX NPs in MCF-7/Adr cells was about 5 μM. Therefore, this study provides a potentially effective strategy against cancer therapeutic resistance.
研究领域:
肿瘤学
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药理学
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纳米医学
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分子生物学
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转化医学
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药物代谢
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产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Yao Peng,Jiaqi Lu,Ru Li,Yi Zhao,Li Hai,Li Guo,Yong Wu
Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.
研究领域:
药学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Jiaqi Lu,Ru Li,Binsong Mu,Yao Peng,Yi Zhao,Yuesen Shi,Li Guo,Li Hai,Yong Wu
A type of pH-sensitive multi-targeted brain tumor site-specific liposomes (Lip-CTPP) co-modified with p -hydroxybenzoic acid (p-HA) and triphenylphosphonium (TPP) were designed and prepared to co-load doxorubicin (DOX) and lonidamine (LND). Lip-CTPP are promising potential carriers to exert the anti-glioma effect of DOX and LND collaboratively given the following features: 1) Lip-CTPP have a good pharmacokinetic behavior; 2) Lip-CTPP can cross the blood-brain barrier (BBB) and recognize tumor cells through the affinity of p-HA and dopamine/sigma receptors; 3) Lip-CTPP are highly positive charged once the acid-sensitive amide bonds are cleaved in endo/lysosomes to expose TPP and protonate amine groups; 4) the positive charged Lip-CTPP escape from endo/lysosomes and accumulate in mitochondria through electrostatic adsorption; 5) DOX and LND are released and synergistically increase anti-tumor efficacy. Our in vitro and in vivo results confirmed that Lip-CTPP could greatly elevate the inhibition rate of tumor cell proliferation , migration and invasion, promote apoptosis and necrosis, and interfere with mitochondrial function. In addition, Lip-CTPP could significantly prolong the survival time of glioma bearing mice, narrow the tumor region and inhibit the infiltration and metastasis capability of glioma cells. Collectively, Lip-CTPP are promising nano formulations to enhance the synergistic effect of DOX and LND in glioma treatment.
研究领域:
药学
·
神经科学
·
肿瘤学
·
药理学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Qishu Jiao,Yaxin Zheng,Qinqing Xie,Xuan Luo,Shuyao Zhou,Shicheng Pei,Tingting Zhang,Xiaoxing Wu,Keming Xu,Wenying Zhong
Photodynamic therapy (PDT) is an effective approach for treating melanoma. However, the photosensitizers employed in PDT can accumulate in healthy tissues, potentially causing harm to normal cells and resulting in side effects such as heightened photosensitivity. To address this, an activatable photosensitizer (PSD) by linking PpIX with a fluorescence quencher using a disulfide bond is designed. PSD responded to endogenous GSH, showing high selectivity for A375 cells. To enhance PSD's bioavailability and anticancer efficacy, an enzyme-responsive nanoplatform based on a lonidamine-derived self-assembling peptide is developed. Initially, PSD and the peptide self-assembled into nanoparticles, displaying potent tumor targeting of PSD in vivo. Upon cell uptake, these nanoparticles specifically responded to elevated cathepsin B, causing nanoparticle disintegration and releasing PSD and lonidamine prodrug (LND-1). PSD is selectively activated by GSH for cancer-specific fluorescence imaging and precision PDT, while LND-1 targeted mitochondria, forming a fibrous lonidamine depot in situ and intensifying photosensitizer's cytotoxicity through ROS generation, mitochondrial dysfunction, and DNA damage. Notably, intravenous administration of LND-1-PEG@PSD with light irradiation significantly suppressed A375-xenografted mouse tumor growth, with minimal systemic toxicity. Together, the synergy of activatable photosensitizer and enzyme-responsive nanoplatform elevates PDT precision and diminishes side effects, showcasing significant potential in the realm of cancer nanomedicine.
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2019
·
IF 4.213
Xin Jin,Jianping Zhou,Zhenhai Zhang,Huixia Lv
Synergistic combination therapy involving the integration of chemotherapeutics and chemosensitizers into micelles has demonstrated great potential for tumor-specific location release. Here, the natural product betulinic acid (BA) and chemical drug lonidamine (LN) were used as chemosensitizers in combination with doxorubicin (DOX) for ovarian cancer treatment. We designed pH-sensitive peptide derivatives and constructed an all-in-one multifunctional multidrug pH-sensitive targeting delivery system for the synergistic co-delivery of DOX and BA (or LN). The combination of DOX and BA was found to elicit better therapeutic effects and lower cardiotoxicity than the DOX and LN combination in Skvo3 cells. Further, loading DOX/BA into the present micellar systems enabled burst release at the tumor location, leading to enhanced anti-tumor effects and reduced off-target effects. More importantly, DOX/BA micelles elicited fewer adverse effects on cardiac function and leukocyte counts in Skvo3 subcutaneous xenograft models. These features suggest that the designed micelles represent a promising multifunctional strategy for the efficient treatment of ovarian cancer.
研究领域:
药学
·
癌症研究
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）