查找使用阿拉丁产品的科研文献

“On/off”-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX

Shuaijun Li,Caiting Meng,Qian Hao,Ruina Zhou,Luyao Dai,Yucheng Guo,Sitong Zhao,Xin Zhou,Chunju Lou,Ji Xu,Peng Xu,Jinfan Yang,Yifan Ding,Yanni Lv,Shengli Han,Shuai Li,Jing Li,Huafeng Kang,Zhengtao Xiao,Mingqian Tan,Xiaobin Ma,Hao Wu

Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions . In this study, we address these challenges by designing a “on/off” switchable crosslinked paclitaxel (PTX) nanocarrier , BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct “on/off” switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The “off” state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the “on” state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.

Effects of paclitaxel (PTX) prodrug-based self-assembly peptide hydrogels combined with suberoylanilide hydroxamic acid (SAHA) for PTX-resistant cancer and synergistic antitumor therapy

Chang Shu,Eboka Majolene B. Sabi-mouka,Wen Yang,Zhongyang Li,Li Ding

In this work, we designed a self-assembly peptide hydrogel encapsulated paclitaxel (PTX) and suberoylanilide hydroxamic acid (SAHA) for cancer co-delivery (Nap–PTX–SAHA). The hydrogels exhibited uniform nanofibers that entangle to form stable networks and pore microstructures (about 140–180 nm) resulting in absorption and storage of hydrophobic drugs. The circular dichroism (CD) spectra of hydrogels exhibit β-turn-like features. Nap–PTX–SAHA hydrogels achieved control over different types of drugs loading and released by diffusion and relaxation processes. Hydrogels exhibited better therapeutic effect and greater synergetic effect compared to the free drugs in vitro and in vivo. Injection of the hydrogels appears to achieve long-term drug release with higher efficacy and better biocompatibility than free drugs. As for the drug biodistribution studies in tumor-bearing mice, the PTX and SAHA from Nap–PTX–SAHA gels uptake in liver, lung and tumor were more than that of free PTX and SAHA. In comparison with free PTX or SAHA, the Nap–PTX–SAHA gels lower the uptake of released drug significantly in the heart, spleen, and kidney to reduce the cardiotoxicity and renaltoxicity. In conclusion, the Nap–PTX–SAHA gels certainly reduce the side effects of PTX and SAHA, enhance synergistic anticancer effects and suppress the drug resistance of PTX. This strategy can be a basis for designing appropriate clinical trials and will hold promise in nanomedicine for different drug combinations.

Cell-Penetrating Peptide Modified PEG-PLA Micelles for Efficient PTX Delivery

Qi Shuai,Yue Cai,Guangkuo Zhao,Xuanrong Sun

On account of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, amphiphilic block copolymer-based micelles have been widely utilized for chemotherapy drug delivery. In order to further improve the antitumor ability and to also reduce undesired side effects of drugs, cell-penetrating peptides have been used to functionalize the surface of polymer micelles endowed with the ability to target tumor tissues. Herein, we first synthesized functional polyethylene glycol-polylactic acid (PEG-PLA) tethered with maleimide at the PEG section of the block polymer, which was further conjugated with a specific peptide, the transactivating transcriptional activator (TAT), with an approved capacity of aiding translocation across the plasma membrane. Then, TAT-conjugated, paclitaxel-loaded nanoparticles were self-assembled into stable nanoparticles with a favorable size of 20 nm, and displayed a significantly increased cytotoxicity, due to their enhanced accumulation via peptide-mediated cellular association in human breast cancer cells (MCF-7)in vitro. But when further usedin vivo, TAT-NP-PTX showed an acceleration of the drug’s plasma clearance rate compared with NP-PTX, and therefore weakened its antitumor activities in the mice model, because of its positive charge, its elimination by the endoplasmic reticulum system more quickly, and its targeting effect on normal cells leading towards being more toxic. So further modification of TAT-NP-PTX to shield TAT peptide’s positive charges may be a hot topic to overcome the present dilemma.Keywords:cell-penetrating peptide;nanoparticles;active tumor targeting;PEG-PLA

Overexpression of hsa_circ_0002874 promotes resistance of non-small cell lung cancer to paclitaxel by modulating miR-1273f/MDM2/p53 pathway

Jianhao Xu,Liwei Ni,Fenglun Zhao,Xiaoxiao Dai,Jialong Tao,Jia Pan,Aiming Shi,Zhu Shen,Cunjin Su,Yusong Zhang

Background: This study aimed to investigate the aberrant expression of hsa_circ_0002874 in non-small cell lung cancer (NSCLC) and elucidate associated molecular mechanisms that influence apoptosis and induce paclitaxel (PTX) resistance. Methods: Inhibitors were used to downregulate circRNA or miRNA expression. pCDNA plasmid transfection and mimics were used to upregulate circRNA or miRNA expression. Dual-luciferase reporter assays were conducted to evaluate interactions between miR1273f and MDM2. Xenograft tumor models were used to assess the effect of hsa_circ_0002874 and miR1273f on tumor growth. NSCLC tissues and matched non-cancerous tissues were also collected for correlation analysis. Results: hsa_circ_0002874 acts as a sponge for miR1273f which targets MDM2/P53. The stability of the hsa_circ_0002874/miR1273f/MDM2/P53 pathway was verified by upregulating and downregulating the expression of hsa_circ_0002874 and miR1273f. hsa_circ_0002874 downregulation or miR1273f upregulation reversed the resistance of the A549/Taxol cells in xenograft models. The expression of hsa_circ_0002874 was high, and the level of MDM2 was low in NSCLC tissues. P53 was only weakly expressed in NSCLC tissues with high expression of MDM2. Conclusions: hsa_circ_0002874 is strongly expressed in NSCLC tissues and maybe a potential marker for PTX resistance. hsa_circ_0002874 downregulation could regulate miR1273f/MDM2/P53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo .

PTX-loaded, polysorbate 80-functionalized brain-targeting pullulan nanoparticles for drug delivery

Huabing Yuan,Lu Han,Hao Deng,Yue Tan,Yi Yang,Yi Liu,Jiaxin Ying,Mengqi Fang,Hui Wei,Zhihe Tao

Brain-targeted drug delivery remains a major challenge in pharmaceutical research. In this study, four types of polysorbate 80 and cholesterol-modified pullulan polymers (CHPP) were synthesized and self-assembled into nanoparticles (CHPP NPs) for brain drug delivery. The properties of these NPs, including brain targeting efficiency, were systematically evaluated to investigate the influence of polymer modification on their performance. The hydrophobicity of the polymers increased with the degree of cholesterol substitution, which in turn led to a reduction in nanoparticle size. Furthermore, higher hydrophobicity contributed to an increased drug loading capacity for paclitaxel (PTX) and a more sustained drug release profile. In vivo fluorescence imaging revealed that formulations with higher levels of polysorbate 80 and cholesterol modification exhibited significantly enhanced brain targeting efficiency compared to other variants. The PTX-loaded CHPP NPs (PTX-CHPP NPs) demonstrated potent cytotoxicity and inhibitory effects against SJ-GBM2 glioma cells in vitro, underscoring their potential as a promising platform for brain-targeted drug delivery. These findings provide valuable insights for the rational design of brain-targeting nanocarriers.

Targeted delivery of PTX by lactoferrin-modified nanoemulsions for the treatment of glioblastoma

Haiming Huang,Jiyong Peng,Zhiting Gao,Yongtong Huang,Wenyang Song,Wenhao Wu,Song Gao,Songsen Chen,Qingchun Xie,Shu Zhang,Jiu Wang

Glioblastoma treatment is hindered by the blood-brain barrier (BBB), which limits the penetration and accumulation of chemotherapeutic agents. Paclitaxel (PTX), an effective chemotherapeutic drug, faces clinical challenges due toits poor solubility and restricted ability to traverse the BBB. Consequently, there is an urgent need for advanced drug delivery systems to facilitate the efficient and safe translocation of PTX across the BBB. In this study, PTX was encapsulated within nanoemulsions (NEs) conjugated to lactoferrin (Lf) via electrostatic interactions, followed by the optimization of its formulation. To investigate cellular uptake and BBB penetration, fluorescent dye coumarin 6 (C6) was incorporated into NEs. Uptake was evaluated in GL261 cells and BBB penetration in hCMEC/D3 cells. Further studies were conducted on the biodistribution in mice and the therapeutic efficacy in murine intracranial glioblastoma model. Characterization of PTX@Lf-NE demonstrated stability, biological safety, and favorable release properties. Notably, the fluorescence intensity of C6@Lf-NE was twice of C6@NE in one hour post-administration, and the drug uptake rate decreased with the addition of free Lf, suggesting that Lf promotes the ability of NEs to traverse the BBB. In vivo distribution further revealed that Lf-NE increased brain distribution while reduced accumulation in other organs. In the glioblastoma model, it was found that the bioluminescent intensity of PTX@Lf-NE was significantly decrease than that of PTX@NE on the 15th day of administration, indicating that the modification with Lf facilitated the targeted delivery of PTX and enhanced its therapeutic efficacy. This study successfully designed and developed an effective drug delivery system for glioblastoma treatment, which improves the translocation of drugs across the BBB.

A Novel Drug-Carrier Based on CMC/MATPP-PTX(CTP) and In Vitro Release

ChengHong Huang,Hong Tang,Shu Jiang,Hongjie Chen,Xiaorong Huang,Kangrui Wang,Ying Fang,Rongrong Men,Jie Gao

pH-responsive nanocomplex for active transport of aPD-1 and PTX to enhance cancer chemoimmunotherapy

Yating Qin,Yan Lin,Chao Tian,Yujie Qi,Shuling Wang,Xiaoyuan Chen,Wenxing Gu

Immune checkpoint blockade (ICB) therapy has emerged as a promising avenue for the treatment of malignant tumors. Nonetheless, the efficacy of this approach is constrained by low anti-tumor immunity and restricted intratumoral delivery of immune checkpoint inhibitors (ICIs) in solid tumors. In this study, a pH-responsive nanocomplex (BRM/PTX/aPD-1) was developed for the active transport of aPD-1 and PTX, thereby enhancing cancer chemoimmunotherapy. BRM/PTX/aPD-1 was prepared by using dynamic and reversible benzoic-imine bonds cross-linked bovine albumin (BSA), anti-PD-1 antibody (aPD-1) and PTX-loaded polylysine dendrimers. In the acidic tumor microenvironment, BRM/PTX/aPD-1 exhibited a charge reversal from negative to positive due to the hydrolysis of the β-carboxylic amide structure, which triggered cation-induced transcytosis. This process enabled active transport of adequate amounts of BRM/PTX/aPD-1 to the tumor parenchyma, where it was degraded by further hydrolysis of benzoic-imine bonds and effectively released aPD-1 and PTX. The nanocomplex demonstrated notable intratumoral permeability both in vitro and in vivo , particularly enhancing the delivery of aPD-1. Additionally, the nanocomplex showed robust anti-tumor activity in an orthotopic breast cancer model, significantly inhibiting tumor proliferation and preventing the progression of lung metastasis. This pH-responsive nanocomplex presents a promising platform for improved intratumoral delivery of ICIs and emerges as a practical solution for overcoming tumor immunosuppression.

Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment

Hao Cai,Yufan Xiang,Yujun Zeng,Zhiqian Li,Xiuli Zheng,Qiang Luo,Hongyan Zhu,Qiyong Gong,Zhongwei Gu,Yanhui Liu,Hu Zhang,Kui Luo

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd 3+ ) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability

Jinzhu Zhao,Leilei Li,Zhijia Wang,Linlin Li,Mingjing He,Shuhua Han,Yalong Dong,Xiaojie Liu,Wen Zhao,Yu Ke,Cong Wang

Cancer drug resistance is a formidable obstacle that enhances cancer stem-like cell properties, tumour metastasis and relapse. Luteolin (Lut) is a natural flavonoid with strong antitumor effects. However, the underlying mechanism(s) by which Lut protects against paclitaxel-resistant (PTX-resistant) cancer cell remains unknown. Herein, we found that Lut significantly attenuated the stem-like properties of PTX-resistant cancer cells by downregulating the expression of SOX2 protein. Additionally, further study showed that Lut could inhibit the PI3K/AKT pathway to decrease the phosphorylation level of AKT(S473) and UBR5 expression, which is an ubiquitin E3 ligase that promotes SOX2 degradation. In addition, Lut also inhibited PTX-resistant cancer cell migration and invasion by blocking epithelial-mesenchymal transition (EMT) . Importantly, Lut inhibited the tumorigenic ability of oesophageal PTX-resistant cancer cells and showed no obvious toxicity in vivo. Thus, Lut has potential as a promising agent for drug-resistant oesophageal cancer therapy.

Precise ratiometric loading of PTX and DOX based on redox-sensitive mixed micelles for cancer therapy

Dujuan Zhao,Jilian Wu,Chuanxiang Li,Huiyuan Zhang,Zhonghao Li,Yuxia Luan

PTX and DOX have different anticancer mechanisms. The combination of the two anticancer drugs could synergically enhance their anticancer effect, but simultaneously accompanied by severe side effects. In the present study, we constructed a mixed micelle system based on redox-sensitive mPEG-SS-PTX and mPEG-SS-DOX conjugate. The drug delivery system has a fixed and high drug loading content of 24.2% (PTX   ∼   14.8% and DOX   ∼   9.4%) with a precise ratio of PTX and DOX to realize the synchronized and controlled release. The mixed micelle has an average size of 93.3   nm with a narrow distribution, suitable for passive targeting to tumor tissues by the EPR effect. In vitro release profile and in vitro anticancer results show the mixed micelles have obvious redox-sensitive release properties in reducing environment and have a significant cytotoxicity to A549 and B16 cells. Importantly, in vivo study shows the mixed micelles have no obvious side effect on mice compared to free PTX/DOX samples during the treatment. Therefore, the constructed redox-sensitive mixed micelle is a promising drug delivery system for cancer therapy.

Construction and synergistic effect of a CGT-Cls-PTX/CM nanocodelivery system targeting the tumor microenvironment

Yun Kong,Jing Zhao,Beihua Xu,Xiaoyue Yang,Lingjie Zhang,Jin Tao,Ying Hu

Immunosuppression within the tumor microenvironment (TME) is a major factor driving pancreatic cancer progression and therapeutic resistance. To address this challenge, we developed a nano-codelivery system, CGT (Cilengitide)-Cls-PTX (paclitaxel)/CM (cell membrane), for the co-delivery of PTX and tumor cell lysate-derived antigens from pancreatic cancer cells (from human pancreatic cancer PANC-1 and mouse pancreatic cancer PANC02 cells). The system was constructed by synthesizing an integrin αvβ3-targeting lipid, DSPE-PEG2000-CGT, and fusing PTX-loaded liposomes with pancreatic cancer cell membranes. This strategy enables preferential accumulation in the TME, where tumor antigens are released to stimulate dendritic cell (DC) maturation and relieve TME immunosuppression, thereby achieving synergistic antitumor efficacy via PTX-mediated tumor cell killing and antigen-induced immune activation. Physicochemical characterization by 1H-nuclear magnetic resonance, transmission electron microscopy, and Western blot confirmed successful synthesis and membrane fusion. Immunostimulatory activity was evaluated using ELISA, flow cytometry, and co-culture assays, and therapeutic efficacy was assessed in a PANC02 murine pancreatic cancer model with Cls-PTX as the control. CGT-Cls-PTX/CM significantly enhanced DC maturation, upregulated co-stimulatory molecules (CD80, CD86), and promoted secretion of interleukin-6 (IL-6) and interleukin-12 (IL-12). Furthermore, it increased CD4+ and CD8+ T-cell proliferation, elevated interferon-γ (IFN-γ) production, suppressed transforming growth factor-β, and facilitated cytotoxic T lymphocyte infiltration into tumor tissues. Overall, CGT-Cls-PTX/CM effectively remodels the immunosuppressive TME, achieving synergistic antitumor effects through combined chemotherapy and immune modulation. This strategy offers a promising approach for enhancing immunotherapeutic efficacy against pancreatic ductal adenocarcinoma, a prototypical ‘cold’ tumor resistant to immune checkpoint therapy.