Nitroreductases and Azoreductases

Zbáida, Shmuel

doi:10.1002/0470846305.ch16

Cited by 10 publications

(3 citation statements)

References 20 publications

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“…Our data supports the hypothesis that the combination of NAcGal-mediated targeting, PEGylation (which is known to limit distribution to off-target organs[ 62 , 63 ]), and a particle size profile that disables free diffusion across intact vasculature[ 64 ] is able to spare P1 and P2 particles from cardiac distribution. Further, we have previously shown that the enzyme-dependent release of DOX from L3-DOX and L4-DOX linkages does not occur in cardiomyocytes, due to the enzymes being solely of hepatic origin,[ 65 – 67 ] and as such we saw no resulting toxicity towards cardiomyocytes. [ 26 ] This suggests that even if P1/P2 particles were to distribute to heart tissue in vivo , DOX release would not occur and therefore no decrease in cardiac function should be observed.…”

Section: Resultsmentioning

confidence: 72%

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

et al. 2017

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Hepatocellular carcinoma (HCC) is the 2 nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3-or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1-and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1-and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/ P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.

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Section: Resultsmentioning

confidence: 72%

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

et al. 2017

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“…Previous studies have shown that microsomal azoreductase enzymes highly expressed in hepatic cancer cells can cleave azo bonds to achieve controlled release of drugs via NADPH-dependent mechanism. [57,58] This study used PBS containing rat liver microsomes and NADPH at pH 6.5 to simulate TME. As shown in Figure 1d, without any stimuli (pH 7.4), <20% of diacerein was released after 48 h incubation.…”

Section: Preparation and Characterization Of Ngs And Dande@ngsmentioning

confidence: 99%

Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia‐Responsive Nanogels

Luo,

Zeng,

Song

et al. 2023

Adv Healthcare Materials

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Despite the success of immuno‐oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno‐oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia‐responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (‐)‐epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL‐6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD‐L1, restoring the tumor‐killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint‐based immuno‐oncotherapy.

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“…Phospholipases, cancer-associated proteases, kinases, and acetyltransferases have also been studied for triggering drug release. − However, the use of these enzymes still involves certain problems, including complexity, difficulty in synthesizing or extracting the substrate, and resulting high costs, which greatly limit the application of enzyme-response nanocarriers. Azoreductase, which is an oxidation–reduction enzyme in hepatocellular microsomes, can cleave azo bonds in the presence of the coenzyme reduced nicotinamide adenine dinucleotide phosphate (NADPH). − The azo bonds can be utilized as a functional group of the nanocarrier, which has a capacity of specifically responding to the azoreductase in the microsomes of hepatocellular carcinoma cells and working as a trigger to induce the disintegration of the nanocarrier. Moreover, the synthesis of azobenzene compounds is very easy and cheap .…”

Section: Introductionmentioning

confidence: 99%

Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles

Zhang

Wang

Zhang

et al. 2017

ACS Appl. Mater. Interfaces

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Highly effective delivery of therapeutic agents into target cells using nanocarriers and subsequently rapid intracellular release are of great importance in cancer treatment. Here, we developed an enzyme and redox dual-responsive polymeric micelle with active targeting abilities to achieve rapid intracellular drug release. To overcome both its poor solubility in water and instability in the blood circulation, camptothecin (CPT) was chemically conjugated to monomethyl poly(ethylene glycol) (mPEG) via a redox-responsive linker to form polymeric prodrugs. The enzyme-responsive function is achieved by connecting hydrophobic polycaprolactone segments and hydrophilic PEG segments with azo bonds. Additionally, the end of the PEG segment was decorated with phenylboronic acid (PBA), endowing the nanocarriers with active targeting abilities. The dual-responsive targeting polymeric micelles can be generated by self-assembly of a mixture of the polymeric prodrug and enzyme-responsive copolymer. The in vitro drug release profile revealed that CPT was rapidly released from the micelles under a simulated condition similar to the tumor cell microenvironment. In vivo and ex vivo fluorescence imaging indicated that these micelles possess excellent specificity to target hepatoma carcinoma cells. The antitumor effect in mice liver cancer cells (H22) in tumor-bearing Kunming (KM) mice demonstrated that this nanocarrier exhibits high therapeutic efficiency in artificial solid tumors and low toxicity to normal tissues, with a survival rate of approximately 100% after 160 days of treatment.

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Nitroreductases and Azoreductases

Cited by 10 publications

References 20 publications

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model

Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia‐Responsive Nanogels

Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles

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