A Nanoantidote Alleviates Glioblastoma Chemotoxicity without Efficacy Compromise

Tian, Meng; Xing, Rui; Guan, Juan; Yang, Bo-sheng; Zhao, Xin; Yang, Juanjuan; Zhan, Changyou; Zhang, Shiyi

doi:10.1021/acs.nanolett.1c01201

Cited by 19 publications

(11 citation statements)

References 53 publications

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“…To break through the above bottlenecks, the application of innovative nanoparticles along with the drugs, which extract toxic agents from intoxicated organs while don′t affect the anticancer efficacy, [6] may be a promising alternative strategy to improve the tolerance of patients and even allows a higher dose of drug to be safely used to enhance the treatment efficacy in the lesion regions [7] . Herein, a nano‐detoxicating platform based on methoxy poly(ethylene glycol)−poly(L‐cystine) (PCys 2 n , n =3, 5, and 10) was exploited to reduce the toxicity of CDDP in normal organs.…”

Section: Methodsmentioning

confidence: 99%

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin

Yang

Zou

et al. 2022

Angew Chem Int Ed

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The toxicity of drugs causes various adverse effects in patients. While antidotes that neutralize drug toxicity help reduce systemic damage during clinical therapy, these antidotes are generally accompanied by the loss of drug efficacy. Herein, the spatiotemporally targeted polycystine‐based nanoantidotes were designed as a neutralizer of cisplatin (CDDP) to decrease its toxicity without affecting its anticancer efficacy. The nanoantidotes administered before CDDP selectively accumulated in the liver and kidney and then firmly bound to CDDP through the highly stable Pt−S bond during subsequent chemotherapy. This two‐step administration strategy reduced the level of Pt in normal organs, shortened the half‐life of CDDP in plasma, and increased the tolerance to CDDP. More importantly, the nanoantidotes maintained the anticancer efficacy of CDDP after reducing systemic toxicity, indicating its great potential in expanding the clinical application of CDDP.

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Section: Methodsmentioning

confidence: 99%

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin

Yang

Zou

et al. 2022

Angew Chem Int Ed

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“…However, the concomitant developments of nanotherapies and bioscavengers have opened new perspectives. Nanodetoxification strategies to develop antidotal nanoparticles specifically for detoxification emerged recently. − Nanoparticles containing enzymes or chemicals with high affinity, selectivity and high reactivity toward various toxic molecules are actively expanding. − In the past years, nanomedicine solutions were introduced in the therapeutic arsenal against OP toxicity. We previously proposed oxime-loaded nanoparticles for emergency treatment of OP poisoning. − At the same time, the use of injectable enzymes (bioscavengers) capable of neutralizing OP molecules in the bloodstream appeared as an alternative to classical pre- and post-exposure treatments .…”

Section: Introductionmentioning

confidence: 99%

Enzyme Nanoreactor for In Vivo Detoxification of Organophosphates

Pashirova

Shaihutdinova

Mansurova

et al. 2022

ACS Appl. Mater. Interfaces

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A nanoreactor containing an evolved mutant of Saccharolobus solfataricus phosphotriesterase (L72C/Y97F/Y99F/W263V/I280T) as a catalytic bioscavenger was made for detoxification of organophosphates. This nanoreactor intended for treatment of organophosphate poisoning was studied against paraoxon (POX). Nanoreactors were low polydispersity polymersomes containing a high concentration of enzyme (20 μM). The polyethylene glycol−polypropylene sulfide membrane allowed for penetration of POX and exit of hydrolysis products. In vitro simulations under second order conditions showed that 1 μM enzyme inactivates 5 μM POX in less than 10 s. LD 50 -shift experiments of POX-challenged mice through intraperitoneal (i.p.) and subcutaneous (s.c.) injections showed that intravenous administration of nanoreactors (1.6 nmol enzyme) protected against 7 × LD 50 i.p. in prophylaxis and 3.3 × LD 50 i.p. in post-exposure treatment. For mice s.c.-challenged, LD 50 shifts were more pronounced: 16.6 × LD 50 in prophylaxis and 9.8 × LD 50 in post-exposure treatment. Rotarod tests showed that transitory impaired neuromuscular functions of challenged mice were restored the day of experiments. No deterioration was observed in the following days and weeks. The high therapeutic index provided by prophylactic administration of enzyme nanoreactors suggests that no other drugs are needed for protection against acute POX toxicity. For post-exposure treatment, co-administration of classical drugs would certainly have beneficial effects against transient incapacitation.

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“…A large number of studies show that reducing the expression of MGMT can enhance the efficacy of TMZ (Wang et al., 2021 ). Moreover, the effectiveness of TMZ in clinical treatment is limited because of the following problems: 1) short half-life (Du et al., 2020 ); 2) difficulty of penetrating the BBB (Tian et al., 2021 ); 3) toxic to normal tissues (Jiang et al., 2021 ). Therefore, overcoming resistance of glioma to the chemotherapeutic TMZ is a key method in treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

The nanoprodrug of polytemozolomide combines with MGMT siRNA to enhance the effect of temozolomide in glioma

Zhang

et al. 2022

Drug Delivery

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Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.

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A Nanoantidote Alleviates Glioblastoma Chemotoxicity without Efficacy Compromise

Cited by 19 publications

References 53 publications

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin

Spatiotemporally Targeted Polypeptide Nanoantidotes Improve Chemotherapy Tolerance of Cisplatin

Enzyme Nanoreactor for In Vivo Detoxification of Organophosphates

The nanoprodrug of polytemozolomide combines with MGMT siRNA to enhance the effect of temozolomide in glioma

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