查找使用阿拉丁产品的科研文献

Tuning multiple arms for camptothecin and folate conjugations on star-shaped copolymers to enhance glutathione-mediated intracellular drug delivery

Yun Zhang,Maohua Chen,Xiaoming Luo,Hong Zhang,Chaoyu Liu,Huiyan Li,Xiaohong Li

Micelle behaviors have been studied intensively for linear block copolymers, and amphiphilic polymers with a non-linear architecture, including star polymers, dendrimers, and hyperbranched polymers are showing advantages in the loading of anticancer drugs. In the current study, multiarmed amphiphilic copolymers with drug conjugates were developed for the construction of micelles to alleviate premature drug release during circulation and to achieve glutathione (GSH)-mediated intracellular drug delivery. Folic acid (FA) was grafted on some of the arms of 4-armed poly(ethylene glycol) (4-arm-PEG) as the targeting groups of micelles, and ε-caprolactone (ε-CL) was copolymerized with PEG from the rest of the arms, followed by camptothecin (CPT) conjugation through dithiodipropionic acid. The effect of the number of arms used for FA conjugation and the length of PCL blocks on micelle properties, reductive sensitivity, cellular uptake, and antitumor activities were evaluated. The amphiphilic copolymers with star-shaped miktoarms were self-assembled into micelles with an average size of around 100 nm and critical micelle concentrations (CMCs) as low as 0.8 μg mL−1. The distribution of hydrophobic PCL segments in more arms resulted in micelles with lower CMCs, higher structural stability, and greater sensitivity of CPT release in the presence of GSH. But, the conjugation of FA on fewer arms led to lower FA densities and less efficient cellular uptake of the micelles. In view of the performance of cellular uptake, CPT loading, and reduction-sensitive release, micelles from 4-armed copolymers with FA conjugation on two arms and PCL copolymerization on another two arms resulted in the most significant antitumor activities. It is suggested that the composition and arm structure of amphiphilic copolymers with star-shaped miktoarms show significant effects on micelle behavior, and optimal antitumor activities can be achieved through judicious selection of multiple arms for conjugating targeting groups and chemotherapeutic drugs.

Probing a dipeptide-based supramolecular assembly as an efficient camptothecin delivering carrier for cancer therapy: computational simulations and experimental validations

Mengchi Sun,Xiangyu Zhang,Zisen Gao,Tian Liu,Cong Luo,Yongshan Zhao,Yun Liu,Zhonggui He,Jian Wang,Jin Sun

Short peptide-based supramolecular assemblies have drawn much attention in the field of drug delivery. However, the progress still remains limited owing to the inefficient drug loading capacity of conventional short peptide-based materials. In this study, based on coordinated intramolecular π–π stacking, we customize a dipeptide-based rhein derivative (rhein–diphenylalanine peptide, RDP), which could spontaneously form spherical nanoassemblies for drug delivery. A structure-based virtual screening of a library of small molecules is conducted to identify the suitable compounds which could be effectively delivered by this nanocarrier. Sorted by binding energy results, fifteen superior and five inferior molecules are found. Subsequently, the co-assembly capacity of high-affinity molecules (camptothecin, CPT) and low-affinity molecules (norcantharidin, NCTD) with the dipeptide-based carrier is predicted via dissipative particle dynamics (DPD) simulation. Consistent with computational results, the in vitro experimental results show that CPT-encapsulated nanoassemblies have significant advantages in the particle size distribution and recrystallization-inhibitory effect compared with NCTD. Furthermore, in vivo experiments were conducted to determine whether CPT is precisely delivered to tumor sites by using the dipeptide-based nanoassemblies. The CPT-loaded nanoassemblies show better effects in terms of drug biodistribution and in vivo anti-tumor efficacy compared to free CPT. The cooperative computational and experimental strategies (in vitro and in vivo) used in this work lay a good foundation to systematically understand short peptide-based assemblies for precise drug delivery.

Camptothecin derivatives induce apoptosis and inhibit proliferation of prostate cancer PC-3M cells through downregulation of PI3K/Akt signaling pathway

Yan Zhao,Yijia Zheng,Xin Chen,Rui Du,Zhaowei Yan

Malignant tumors are increasing the human mortality rate year by year, so there is an urgent need to develop novel and highly effective drugs. Camptothecin (CPT) is a natural medicinal product with broad-spectrum antitumor activity. In this study, 11 CPT derivatives were synthesized. Their antitumor activities were evaluated by CCK-8, morphological observation, plate cloning, scratching, DAPI staining, cell cycle, and apoptosis. The conformational relationships were also analyzed by molecular docking and 3D-QSAR. The results showed that the CPT derivatives showed significant inhibitory effects on all five tumor cell lines, A549, HepG2, MCF-7, HemECs, and PC-3M, with the best inhibitory ability against PC-3M in prostate cancer. Among all derivatives, compound 5 had the lowest IC50 value of 0.0881 μM. In addition, compound 5 regulated the downstream cascade response by inhibiting the PI3K-Akt signaling pathway, causing cycle arrest and apoptosis. The predicted results of molecular docking and 3D-QSAR were consistent with those of the experimental group. This demonstrates the anti-tumor potential of compound 5.

Silane-modified cellulose molecularly imprinted microspheres as solid-phase extraction sorbents for selective camptothecin isolation from Camptotheca acuminata crude extracts

Linan Sun,Ming Qu,Jingru Zhao,Chengbo Gu,Xue Wu,Han Yang,Yujie Fu

CPT-enriching molecularly imprinted materials have been developed. • CCS-Si and MIP-CPT exhibit high selectivity for CPT. • The efficiency of the molecularly imprinted extraction column can reach 89.45%. Camptothecin (CPT), a potent anticancer quinoline alkaloid derived from plant resources, is conventionally purified through multi-step processes with low selectivity, high solvent consumption and unsatisfactory recovery. In this study, a novel bio-based surface-imprinted adsorbent (CCS-Si&MIP-CPT) was rationally designed and fabricated using porous cellulose-silica hybrid microspheres as the support matrix, with CPT as the template molecule and methacrylic acid as the functional monomer. The physicochemical structure of the as-prepared material was fully characterized, and its adsorption kinetics, isotherms, selective recognition mechanism and reusability were systematically investigated. Furthermore, the material was applied as a solid-phase extraction (SPE) filler for the purification of CPT from crude camptotheca seed extracts, and its performance was benchmarked against established purification methods. The results show that the adsorption behaviour of CCS-Si&MIP-CPT toward CPT is in good agreement with the Langmuir isotherm and the pseudo-second-order kinetic model. Combined with molecular structure comparison of CPT analogs, the selective recognition mechanism was comprehensively elucidated from three perspectives: hydrogen-bonding functional group matching, steric hindrance effect of substituents, and complementarity of molecular size and overall shape. The renewable carrier design and its cyclic stability not only show potential for application in green separation technologies for natural medicine development, but also provide a theoretical foundation for the high-value utilization of plant resources.

Camptothecin prodrug nanomicelle based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake

Ya Gao,Yi Xiao,Shiyuan Liu,Jiahui Yu

Camptothecin Inhibits Neddylation to Activate the Protective Autophagy Through NF-κB/AMPK/mTOR/ULK1 Axis in Human Esophageal Cancer Cells

Heng Yongqing,Liang Yupei,Zhang Junqian,Li Lihui,Zhang Wenjuan,Jiang Yanyu,Wang Shiwen,Jia Lijun

The neddylation pathway is overactivated in esophageal cancer. Our previous studies indicated that inactivation of neddylation by the NAE inhibitor induced apoptosis and autophagy in cancer cells. Camptothecin (CPT), a well-known anticancer agent, could induce apoptosis and autophagy in cancer cells. However, whether CPT could affect the neddylation pathway and the molecular mechanisms of CPT-induced autophagy in esophageal cancer remains elusive. We found that CPT induced apoptosis and autophagy in esophageal cancer. Mechanistically, CPT inhibited the activity of neddylation and induced the accumulation of p-IkBa to block NF-κB pathway. Furthermore, CPT induced the generation of ROS to modulate the AMPK/mTOR/ULK1 axis to finally promote protective autophagy. In our study, we elucidate a novel mechanism of the NF-κB/AMPK/mTOR/ULK1 pathway in CPT-induced protective autophagy in esophageal cancer cells, which provides a sound rationale for combinational anti-ESCC therapy with CPT and inhibition AMPK/ULK1 pathway.

Rational Design of a New Self-Codelivery System from Redox-Sensitive Camptothecin–Cytarabine Conjugate Assembly for Effectively Synergistic Anticancer Therapy

Wenxiu He,Xu Hu,Wei Jiang,Ruiling Liu,Di Zhang,Jing Zhang,Zhonghao Li,Yuxia Luan

Herein, two careful selected anticancer drugs camptothecin (CPT) and cytarabine (Ara-C) with different biological action mechanisms and different water solubility are conjugated together through a glutathione (GSH) cleavable disulfide bond to construct a redox-sensitive drug–drug conjugate, which can self-assemble into nanoparticles, thus notably improving the water solubility of CPT and the cell membrane permeability of Ara-C. Compared with free drugs, the self-assembled CPT-ss-Ara nanoparticles can concentrate in tumor tissues through the enhanced permeability and retention (EPR) effect, then they can be rapidly internalized by tumor cells and degrade into free drugs for killing the tumor cells when exposed to the reductive environment (GSH) of tumor cells, thereby reducing the injury to normal cells. Meanwhile, the CPT-ss-Ara nanoparticles can effectively protect CPT and Ara-C molecules from biological inactivation before their arrival in tumor microenvironment since free CPT and Ara-C are easy to partly lose their therapy efficacy due to their structure degradation in blood circulation. The in vitro and in vivo anticancer experimental results indicate that simultaneous release of free CPT and Ara-C can realize synergistic chemotherapy effects, thus markedly improve their anticancer activity. Therefore, our designed carrier-free, redox-sensitive CPT-ss-Ara nanoparticles might have promising clinical application to combat cancers.

GSH-activatable Camptothecin Prodrug-loaded Gold Nanostar Coated with Hyaluronic Acid for Targeted Breast Cancer Therapy via Multiple Radiosensitization Strategies

Jin-Xiang Chen,Ying-Ke Hou,Bin Sun,Rong tian Li,Wei Men,Wen-Hua Zhang,Nuan Jia,Ming Chen,Xiaoyan Tang

Breast cancer has overtaken lung cancer to rank as the top malignant tumor in terms of incidence. Herein, gold nanostar (denoted as AuNS) is used for loading disulfide-coupled camptothecin-fluorophore prodrugs (denoted as CPT-SS-FL) to form the nanocomposite of AuNS@CPT-SS-FL (denoted as AS), which, in turn, further encapsulated with hyaluronic acid (HA) to give the final nanoplatform of AuNS@CPT-SS-FL@HA (denoted as ASH). ASH effectively carries the prodrug and targets the CD44 receptor on the surface of tumor cells. The endogenously overexpressed glutathione (GSH) in tumor cells breaks the disulfide bond to activate the prodrug and release the radiosensitizer drug camptothecin (CPT) and the fluorescent imaging reagent rhodamine derivative as fluorophore (FL). The released FL can track the precise release position of radiosensitizer camptothecin in tumor cells in real time. While the AuNS has strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79). At the same time, AuNS can alleviate the tumor microenvironment (TME) hypoxia through its mild photothermal therapy (PTT). Therefore, through the multiple radiosensitizing effects of GSH depletion, high atomic coefficient of Au, and hypoxia alleviation, accompanied by the radiosensitizer camptothecin, the designed ASH nanoplatform can effectively induce strong immunogenic cell death (ICD) at the tumor site via radiosensitizing therapy combined with PTT. This work provides a new way of constructing a structurally compact and highly functionalized hierarchical system toward efficient breast cancer treatment through ameliorating TME with multiple modalities.

Selective inhibition of glycolysis in hepatic stellate cells and suppression of liver fibrogenesis with vitamin A-derivative decorated camptothecin micelles

Li Xiang,Xin Wang,Qiangqiang Jiao,Yaru Shao,Rui Luo,Jie Zhang,Xiaotong Zheng,Shaobing Zhou,Yuping Chen

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl 4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. Statement of significance Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl 4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.

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.

Engineering of smart nanostructured lipid carriers encapsulated in gold nanocomposites and camptothecin for synergistic photothermal and chemotherapy treatment of ovarian cancer

Fan Yibing,Wen Jiayu,Shi Li,Dai Yingqing

Ovarian cancer describes a group of disorders that start in the ovaries or adjacent fallopian tubes and peritoneum. It is becoming increasingly clear that chemotherapy alone is ineffective for ovarian cancer. For dual chemo/photothermal treatment, we effectively developed camptothecin (CPT) and gold nanocomposites (AuNCs)-loaded nanostructured lipid carriers (CPT + AuNCs@NSLCs). Gold nanocomposites (AuNCs) of varying shapes and sizes (gold nanorods [AuNRs] and the gold nanospheres [AuNSs]) were placed in NSLCs to take advantage of their photothermal capability and to theorize the blend of drug delivery systems for chemo/photothermal treatment. Before and after being subjected to near-infrared light (808 nm), NSLCs were tested for their ability to spontaneously release CPT. AuNRs had the maximum heating potential of Δ T  = 22 °C in 5 min with the 19.8 µg Au/mg lipids. HeLa ovarian cancer cells were used to assess the cytotoxic impact of various formulations, and under 5 min of NIR exposure, CPT + AuNRs@NSLCs showed the most significant growth inhibition (81%) of the bunch. It has been discovered that the photothermal capability of AuNCs is directly affected by their structure, that the cytotoxic property of CPT and the local hyperthermia delivered by AuNCs may suggestively improve cellular damage, and that the established advanced nanoformulations have excellent promising as a chemo/photothermal agent. As a result, the results of this research show promise for fabricating a lipid-mediated multifunctional biocompatible nanoplatform applicable to combination treatment and amenable to fine-tuning its features.

Design, Synthesis, and Bioevaluation of Novel Enzyme-Triggerable Cell Penetrating Peptide-Based Dendrimers for Targeted Delivery of Camptothecin and Cancer Therapy

Ruiyao Mai,Bulian Deng,Huiting Zhao,Ling Li,Yuyu Fang,Siming Li,Xin Deng,Jianjun Chen

Novel enzyme-triggerable cell penetrating peptide (ETCPP) dendrimers with a camptothecin (CPT) warhead were designed and synthesized based on an amphiphilic penetrating peptide (FKKFFRKLL, discovered by us before). Among the newly synthesized ETCPP dendrimer conjugates, BL_Oc-SS-CPT (a high-generation dendrimer) exhibited the highest activity with IC50s in the nanomolar range (31–747 nM) against a panel of cancer cells, which is 3–10 times better than that of CPT. BL_Oc-SS-CPT remained intact during transit to target cells and in normal tissues with a plasma half-life of 4.2 h, 2.3-fold longer than that of the monomer (1.8 h). Once reaching the tumor site, BL_Oc-SS-CPT gradually released CPT in the presence of excessive matrix metalloproteinase-2/9 and GSH in cancer cells. Importantly, BL_Oc-SS-CPT exhibited excellent in vivo tumor targeting capability and antitumor efficacy with benign toxicity profiles. Thus, the novel ETCPP dendrimer-based drug delivery system (e.g., BL_Oc-SS-CPT) represents a safe and effective strategy for targeted cancer therapy.