共查询到20条相似文献,搜索用时 46 毫秒
1.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2018,130(29):9236-9240
Recently, PtIV prodrugs have attracted much attention as the next generation of platinum‐based antineoplastic drug candidates. Here we report the discovery and evaluation of monochalcoplatin, a monocarboxylated PtIV prodrug that is among the most cytotoxic PtIV prodrugs to date. Compared with its dicarboxylated counterpart chalcoplatin, monochalcoplatin accumulates astonishingly effectively and rapidly in cancer cells, which is not ascribed to its lipophilicity. The prodrug is quickly reduced, causes DNA damage, and induces apoptosis, resulting in superior cytotoxicity with IC50 values in the nanomolar range in both cisplatin‐sensitive and ‐resistant cells; these IC50 values are up to 422‐fold higher than that of cisplatin. A detailed mechanistic study reveals that monochalcoplatin actively enters cells through a transporter‐mediated process. Moreover, monochalcoplatin shows significant antitumor activity in an in vivo colorectal tumor model. Our study implies a practical strategy for the design of more effective PtIV prodrugs to conquer drug resistance by tuning both cellular uptake pathways and activation processes. 相似文献
2.
Dr. Hana Kostrhunova Dr. Emanuele Petruzzella Prof. Dr. Dan Gibson Prof. Dr. Jana Kasparkova Prof. Dr. Viktor Brabec 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(20):5235-5245
Dual- or multi-action PtIV prodrugs represent a new generation of platinum anticancer drugs. The important property of these PtIV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple-action” prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the PtIV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9 nm (HCT-116) to 74 nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the PtIV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the PtIV prodrug introduced in this study acts as a true “multi-action” prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells. 相似文献
3.
Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin 下载免费PDF全文
Hongdong Shi Qinqin Cheng Siming Yuan Xin Ding Prof. Yangzhong Liu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(46):16547-16554
Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the PtIV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the PtIV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells. 相似文献
4.
Maria V. Babak Yang Zhi Bertrand Czarny Tan Boon Toh Lissa Hooi Edward Kai‐Hua Chow Wee Han Ang Dan Gibson Giorgia Pastorin 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(24):8193-8198
A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. 相似文献
5.
Jun Xiang Ong Carine Shu Qing Lim Hai Van Le Wee Han Ang 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(1):170-173
The PtIV prodrug strategy has emerged as an excellent alternative to tackle the problems associated with conventional PtII drug therapy. However, there is a lack of tools to study how this new class of PtIV drugs are processed at the cellular level. Herein, we report the first ratiometric probe for cisplatin detection and use it to investigate PtIV anticancer complexes in biological systems. The probe was able to distinguish between cisplatin and its PtIV derivatives, allowing us to probe the intracellular reduction of PtIV prodrug complexes. The correlation between the amount of active PtII species available after intracellular reduction of PtIV complexes and their cytotoxicity and the role glutathione plays in the reduction of PtIV complexes were investigated. 相似文献
6.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(38):11697-11702
We developed a novel PtIV prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200–450‐fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40‐fold more selective towards KRAS mutated cells compared to non‐cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90 % of pancreatic adenocarcinomas, 45 % of colorectal cancers, and 35 % of lung adenocarcinomas. The selectivity index, determined by dividing the IC50 value in non‐cancerous cells by that of a cancerous cell line, is two‐fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells. 相似文献
7.
Thirumal Yempala Tomer Babu Subhendu Karmakar Alina Nemirovski Maisaloon Ishan Valentina Gandin Dan Gibson 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(50):18386-18391
Most multi‐action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active drugs. In contrast, succinate‐linked drugs did not readily release the free drugs. The carbonate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Carb)Cl2] was significantly more cytotoxic than the succinate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Suc)Cl2], and more potent and less toxic than gemcitabine, cisplatin, and co‐administration of cisplatin and gemcitabine. 相似文献
8.
Juraj Zajac Vojtech Novohradsky Lenka Markova Viktor Brabec Jana Kasparkova 《Angewandte Chemie (International ed. in English)》2020,59(8):3329-3335
To design an anticancer drug capable of inhibiting not only the proliferation of the differentiated tumor cells but also reducing the tumorigenic capability of cancer stem cells (CSCs), the new PtIV prodrugs with axial cinnamate ligands were synthesized. We demonstrate their superior antiproliferative activity in monolayer and 3D spheroid antiproliferative activity tests using panel of cancer cell lines. An outstanding activity was found against rhabdomyosarcoma cells, one of the most problematic and poorly treatable pediatric tumors. The results also suggest that the released PtII compound inhibits antiproliferative activity of cancer cells by DNA‐damage mediated mechanism; the released cinnamic acid can trigger processes leading to differentiation, making the CSCs more sensitive to killing by the platinum part of the complex. PtIV complex with axial cinnamate ligands is the first PtIV prodrug capable of overcoming CSCs resistance and induce death in both CSCs and bulk cancer. 相似文献
9.
A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance 下载免费PDF全文
Zhigang Wang Zoufeng Xu Prof. Dr. Guangyu Zhu 《Angewandte Chemie (International ed. in English)》2016,55(50):15564-15568
DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA‐damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a PtIV anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin‐induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual‐action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin‐resistant human cancer cells with an up to 88‐fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt‐induced DNA damage as a novel strategy to conquer cisplatin resistance. 相似文献
10.
Dr. Rakesh K. Pathak Christopher D. McNitt Prof. Dr. Vladimir V. Popik Prof. Dr. Shanta Dhar 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(23):6861-6865
The ability to rationally design and construct a platform technology to develop new platinum(IV) [PtIV] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well‐defined chemistry is critical for discovering new platinum‐based therapeutics. With limited numbers of possibilities considering the sensitivity of PtIV centers, we used a strain‐promoted azide–alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single PtIV precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated. 相似文献
11.
Dr. Gregory Thiabaud Rebecca McCall Dr. Guangan He Prof. Jonathan F. Arambula Prof. Zahid H. Siddik Prof. Jonathan L. Sessler 《Angewandte Chemie (International ed. in English)》2016,55(41):12626-12631
Water‐soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co‐incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of PtIV to PtII promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the PtIV species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer‐selective enhancement in the cytotoxicity of PtIV prodrugs. 相似文献
12.
Johannes Karges Thirumal Yempala Mickaël Tharaud Dan Gibson Gilles Gasser 《Angewandte Chemie (International ed. in English)》2020,59(18):7069-7075
PtII complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, PtIV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, RuII polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel PtIV–RuII conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the PtIV centre is reduced to PtII and the axial ligands including the RuII complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi‐target and multi‐action effect with (photo‐)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids. 相似文献
13.
Fluorescence microscopy has emerged as an attractive technique to probe the intracellular processing of Pt‐based anticancer compounds. Herein, we reported the first through‐bond energy transfer (TBET) fluorescent probe NPR1 designed for sensitive detection and quantitation of PtII complexes. The novel TBET probe was successfully applied for ratiometric fluorescence imaging of anticancer PtII complexes such as cisplatin and JM118 in cells. Capitalizing on the ability of the probe to discriminate between PtII complexes and their PtIV derivatives, the probe was further applied to study the activation of PtIV prodrug complexes that are known to release active PtII species after intracellular reduction. 相似文献
14.
Tomer Babu Hiba Ghareeb Dr. Uttara Basu Hemma Schueffl Dr. Sarah Theiner Prof. Petra Heffeter Prof. Gunda Koellensperger Prof. Norman Metanis Prof. Valentina Gandin Prof. Ingo Ott Dr. Claudia Schmidt Prof. Dan Gibson 《Angewandte Chemie (International ed. in English)》2023,62(10):e202217233
AuI-carbene and PtIV−AuI-carbene prodrugs display low to sub-μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt-derived PtIV(phenylbutyrate) complex to a AuI-phenylimidazolylidene complex 2 , yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug PtIV(phenylbutyrate)-AuI-carbene ( 7 ) and the 1 : 1 : 1 co-administration of cisPt: phenylbutyrate: 2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2 , 20 % for cisPt and >30 % for the co-administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser-ablation (LA)-ICP-TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there. 相似文献
15.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(49):15751-15755
Cancer cells produce elevated levels of reactive oxygen species, which has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, in which a prodrug reacts with ROS. However, at low micromolar concentrations of the prodrugs and ROS, the activation is usually inefficient. Herein, we propose and validate a potentially general approach for solving this intrinsic problem of ROS‐dependent prodrugs. In particular, known prodrug 4‐(N ‐ferrocenyl‐N ‐benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted into its lysosome‐specific analogue. Since lysosomes contain a higher concentration of active ROS than the cytoplasm, activation of the prodrug was facilitated with respect to the parent compound. Moreover, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50=3.5–7.2 μm ) and in vivo (40 mg kg−1, NK/Ly murine model) but remained weakly toxic towards non‐malignant cells (IC50=15–30 μm ). 相似文献
16.
Near‐Infrared Light‐Mediated Photoactivation of a Platinum Antitumor Prodrug and Simultaneous Cellular Apoptosis Imaging by Upconversion‐Luminescent Nanoparticles 下载免费PDF全文
Yuanzeng Min Jinming Li Fang Liu Prof. Edwin K. L. Yeow Prof. Bengang Xing 《Angewandte Chemie (International ed. in English)》2014,53(4):1012-1016
Platinum‐based drugs are among the most active antitumor reagents in clinical practice; their application is limited by side effects and drug resistance. A novel and personalized near‐infrared (NIR) light‐activated nanoplatform is obtained by combining a photoactivatable platinum(IV) prodrug and a caspase imaging peptide conjugated with silica‐coated upconversion‐luminescent nanoparticles (UCNPs) for the remote control of antitumor platinum prodrug activation, and simultaneously for real‐time imaging of apoptosis induced by activated cytotoxicity. Upon NIR light illumination, the PtIV prodrug complex is activated at the surface of the nanoparticle and active components are selectively released which display cytotoxicity against human ovarian carcinoma A2780 cells and its cisplatin‐resistant variant A2780cis cells. More importantly, the caspases enzymes triggered by cytotoxicity would effectively cleave the probe peptide, thereby allowing the direct imaging of apoptosis in living cells. 相似文献
17.
Qiyuan Zhou Shu Chen Dr. Zoufeng Xu Gongyuan Liu Shuyuan Zhang Prof. Dr. Zhigang Wang Dr. Man-Kit Tse Dr. Shek-Man Yiu Prof. Dr. Guangyu Zhu 《Angewandte Chemie (International ed. in English)》2023,62(18):e202302156
Although multitargeted PtIV anticancer prodrugs have shown significant activities in reducing drug resistance, the types of bioactive ligands and drugs that can be conjugated to the Pt center remain limited to O-donors. Herein, we report the synthesis of PtIV complexes bearing axial pyridines via ligand exchange reactions. Unexpectedly, the axial pyridines are quickly released after reduction, indicating their potential to be utilized as axial leaving groups. We further expand our synthetic approach to obtaining two multitargeted PtIV prodrugs containing bioactive pyridinyl ligands: a PARP inhibitor and an EGFR tyrosine kinase inhibitor; these conjugates exhibit great potential for overcoming drug resistance, and the latter conjugate inhibits the growth of Pt-resistant tumor in vivo. This research adds to the array of synthetic methods for accessing PtIV prodrugs and significantly increases the types of bioactive axial ligands that can be conjugated to a PtIV center. 相似文献
18.
Dr. Johannes Karges Dr. Thirumal Yempala Mickaël Tharaud Prof. Dan Gibson Dr. Gilles Gasser 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(18):7135-7141
PtII complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, PtIV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, RuII polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel PtIV–RuII conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the PtIV centre is reduced to PtII and the axial ligands including the RuII complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids. 相似文献
19.
Dr. Hana Kostrhunova Dr. Juraj Zajac Dr. Lenka Markova Prof. Viktor Brabec Prof. Jana Kasparkova 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(47):21343-21348
HER2-positive breast cancer is an aggressive subtype that typically responds poorly to standard chemotherapy. To design an anticancer drug selective for HER2-expressing breast cancer, a PtIV prodrug with axial oleate and cinnamate ligands was synthesized. We demonstrate its superior antiproliferative activity in monolayer and 3D spheroid models; the antiproliferative efficiency increases gradually with increasing expression of HER2. The results also suggest that the released PtII compound inhibits the proliferation of cancer cells by a DNA-damage-mediated mechanism. Simultaneously, the released oleic and cinnamic acid can effectively inhibit HER2 expression. To our knowledge, this is the first platinum-based complex inhibiting HER2 expression that does not contain protein or peptide. Moreover, this PtIV prodrug is capable of overcoming the resistance of cancer stem cells (CSCs), inducing death in both CSCs and differentiated cancer cells. Thus, the results substantiate our design strategy and demonstrate the potential of this approach for the development of new, therapeutically relevant compounds. 相似文献
20.
Ganghao Liang Dr. Tumpa Sadhukhan Dr. Samya Banerjee Dongsheng Tang Hanchen Zhang Minhui Cui Nicolás Montesdeoca Dr. Johannes Karges Prof. Dr. Haihua Xiao 《Angewandte Chemie (International ed. in English)》2023,62(22):e202301074
The development of PtIV prodrugs that are reduced into the therapeutically active PtII species within the tumor microenvironment has received much research interest. In order to provide spatial and temporal control over the treatment, there is a high demand for the development of compounds that could be selectively activated upon irradiation. Despite recent progress, the majority of PtIV complexes are excited with ultraviolet or blue light, limiting the use of such compounds to superficial application. To overcome this limitation, herein, the first example of PtIV prodrug nanoparticles that could be reduced with deeply penetrating ultrasound radiation is reported, enabling the treatment of deep-seated or large tumors. The nanoparticles were found to selectively accumulate inside a mouse colon carcinoma tumor upon intravenous injection and were able to eradicate the tumor upon exposure to ultrasound radiation. 相似文献