ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy

Pei, Pei; Sun, Chunyang; Tao, Wei; Li, Jie; Yang, Xianzhu; Wang, Jun

doi:10.1016/j.biomaterials.2018.10.010

Cited by 167 publications

(107 citation statements)

References 41 publications

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“…In particular, H 2 O 2 enrichment in tumor sites (ca. 1 m m ) makes it a superior stimulus for drug release, and it presents stimuli‐responsive release behavior if the chemotherapeutic drugs are conjugated onto the polymers through H 2 O 2 ‐cleavable thioketal or thioether linkages . On this basis, Liu et al.…”

Section: Stimuli‐responsive Drug‐release Nanosystemsmentioning

confidence: 99%

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

Qin

2020

ChemBioChem

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The emergence and development of nanomedicine have alleviated problems existing in traditional chemotherapy drugs, such as short lifetime, concomitant side effects, and weak tumor‐targeting capability. Nevertheless, the further applications of drug‐loaded nanocarriers are still limited by their premature leakage, weak targeting capability, and insufficient intracellular release. In past decades, various nanocarriers, including gold nanoparticles, porous silica nanoparticles, carbon‐based nanoparticles, micelles, liposomes, and polymer–drug conjugates, have been intensively investigated for tumor therapy. Among these, polymer‐based nanocarriers have attracted more attention due to their biocompatibilities and capability of being modified for stimuli‐responsive drug release. In this review, three popular strategies to design and synthesize polymer‐based stimuli‐responsive nanocarriers are discussed. The discussion goes from stimuli‐responsive polymers with responsive backbones or modified by responsive functional groups for drug encapsulation and release to polymer–drug conjugates with responsive covalent linkages. In particular, due to the facile synthetic processes and mild reaction conditions for crosslinked structures, the latest progress in responsive crosslinked structures is emphasized. Finally, future perspectives for these nanomaterials are given, which are expected to provide inspiration for researchers to design more effective and safer tumor‐killing nanomedicines.

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Section: Stimuli‐responsive Drug‐release Nanosystemsmentioning

confidence: 99%

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

Qin

2020

ChemBioChem

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“…108 In 2012, Xia et al 109 Given the relatively slow degradation profile of the thioketal linker under physiologically relevant ROS concentrations in tumor, there is the question of whether there is a way to provide an extra boost to ROS generation at the site of action. Along this line, Wang et al 110 utilized such a thioketal linker to reduce off-site drug leakage in their nanoparticle design. In this design, a ROS-sensitive thioketal linker (TK) was used to link a polyphosphoester with anticancer drug Dox to form PPE-TK-DOX.…”

Section: Thioketal-based Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

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“…Interestingly, the continuous production of ROS (hydroxyl radical, H 2 O 2, and superoxide) by GBM cells is needed for the cells' growth (Li et al, 2016;Hwang et al, 2018), and the design of DDS that trigger the release of anticancer drugs upon ROS stimulus (known as ROS-responsive DDS) could significantly improve the effectivity of chemotherapeutic agents in GBM as confirmed by a number of studies on ROS-responsive polymeric prodrugs in cancer therapy (Yue et al, 2016;Xu et al, 2017;Pei et al, 2019;Wang et al, 2019b). A plethora of ROS-responsive chemical groups have been developed, for example: polypropylene sulfide, selenium and tellurium, polyoxalate, poly(proline), phenyl boronic ester, and more recently thioketal (TK) were used as linkers for the synthesis of ROSresponsive systems.…”

Section: Introductionmentioning

confidence: 98%

Synthesis, Characterization, and In Vitro Studies of an Reactive Oxygen Species (ROS)-Responsive Methoxy Polyethylene Glycol-Thioketal-Melphalan Prodrug for Glioblastoma Treatment

et al. 2020

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Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the brain and averages a life expectancy in diagnosed patients of only 15 months. Hence, more effective therapies against this malignancy are urgently needed. Several diseases, including cancer, are featured by high levels of reactive oxygen species (ROS), which are possible GBM hallmarks to target or benefit from. Therefore, the covalent linkage of drugs to ROS-responsive molecules can be exploited aiming for a selective drug release within relevant pathological environments. In this work, we designed a new ROS-responsive prodrug by using Melphalan (MPH) covalently coupled with methoxy polyethylene glycol (mPEG) through a ROS-cleavable group thioketal (TK), demonstrating the capacity to self-assembly into nanosized micelles. Full chemical-physical characterization was conducted on the polymeric-prodrug and proper controls, along with in vitro cytotoxicity assayed on different GBM cell lines and "healthy" astrocyte cells confirming the absence of any cytotoxicity of the prodrug on healthy cells (i.e. astrocytes). These results were compared with the non-ROS responsive counterpart, underlining the anti-tumoral activity of ROS-responsive compared to the non-ROSresponsive prodrug on GBM cells expressing high levels of ROS. On the other hand, the combination treatment with this ROS-responsive prodrug and X-ray irradiation on human GBM cells resulted in an increase of the antitumoral effect, and this might be connected to radiotherapy. Hence, these results represent a starting point for a rationale design of innovative and tailored ROS-responsive prodrugs to be used in GBM therapy and in combination with radiotherapy.

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ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy

Cited by 167 publications

References 41 publications

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Synthesis, Characterization, and In Vitro Studies of an Reactive Oxygen Species (ROS)-Responsive Methoxy Polyethylene Glycol-Thioketal-Melphalan Prodrug for Glioblastoma Treatment

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