Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors

Altai, Mohamed; Líu, Hao; Ding, Haozhong; Mitran, Bogdan; Edqvist, Per‐Henrik; Tolmachev, Vladimir; Orlova, Anna; Gräslund, Torbjörn

doi:10.1016/j.jconrel.2018.08.040

Cited by 45 publications

(74 citation statements)

References 38 publications

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“…Thus, a drug delivery system can be slowly release, long circulation in vivo was very important, and zein nano drug delivery system was selected. According to the results of our cell experiments, the IC50 of DM1-loaded ZNPs was 0.01237 ng/mL, which was lower than that reported in the literature, demonstrating that DM1-loaded ZNPs are more sensitive to A549 cells ( Reddy et al, 2007;Altai et al, 2018). We speculate that in this study, DM1-loaded ZNPs is sensitive to A549 cells and has strong antitumor growth effect.…”

Section: Discussioncontrasting

confidence: 42%

Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer

et al. 2019

Drug Delivery

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2020) Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer, Drug Delivery, 27:1, 100-109, ABSTRACT Purpose: Maytansine (DM1) is a potent anticancer drug and limited in clinical application due to its poor water solubility and toxic side effects. Zein is widely used in nano drug delivery systems due to its good biocompatibility. In this study, we prepared DM1-loaded zein nanoparticles (ZNPs) to achieve tumor targeting and reduce toxic side effects of DM1. Methods: ZNPs were prepared by phase separation and Box-Behnken design was used to optimize the formulation. Then, confocal fluorescence microscope and flow cytometry were used to determine cellular uptake of ZNPs. A549 cells were cultured in vitro to study cytotoxicity and used to establish tumor xenografts in nude mice. Biodistribution and antitumor activity of ZNPs were performed in vivo experiments. In addition, we also performed histological and immunohistochemical examinations on tumors and viscera. Results: The optimal prescription was obtained by using 120 lL zein added to 2 mL water under stirring in 300 rpm. The encapsulation efficiency and drug loading were 82.97 ± 0.80% and 3.32 ± 0.03%, respectively. We found that DM1-loaded ZNPs have a strong inhibitory effect on A549 cells, which stemmed from the ability of ZNPs to enhance cellular uptake. Furthermore, we demonstrated that DM1-loaded ZNPs exhibits a better antitumor efficacy than DM1, which tumor inhibition rate were 97.3% and 92.7%, respectively. The biodistribution revealed that ZNPs could targeted to tumor. Finally, we confirmed by histological that DM1-loaded ZNPs are nontoxic. Conclusion: DM1-loaded ZNPs have considerable antitumor activity. Thus, DM1-loaded ZNPs are a promising treatment of non-small cell lung cancer. ARTICLE HISTORY

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Section: Discussioncontrasting

confidence: 42%

Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer

et al. 2019

Drug Delivery

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“…Even though the actual half-life was not quantified, it is obvious from the marked increase in blood concentration after 24 h, that addition of the ABD increased the half-life. Typically, addition of an ABD extends the half-life through interaction with albumin [28], but other factors, such as higher stability in serum conferred by genetic fusion to the ABD, cannot be ruled out. There are alternatives to using an ABD for half-life extension [29], e.g.…”

Section: Discussionmentioning

confidence: 99%

An in vivo half-life extended prolactin receptor antagonist can prevent STAT5 phosphorylation

Alkharusi

Norstedt

et al. 2019

PLoS ONE

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Increasing evidence suggests that signaling through the prolactin/prolactin receptor axis is important for stimulation the growth of many cancers including glioblastoma multiforme, breast and ovarian carcinoma. Efficient inhibitors of signaling have previously been developed but their applicability as cancer drugs is limited by the short in vivo half-life. In this study, we show that a fusion protein, consisting of the prolactin receptor antagonist PrlRA and an albumin binding domain for half-life extension can be expressed as inclusion bodies in Escherichia coli and efficiently refolded and purified to homogeneity. The fusion protein was found to have strong affinity for the two intended targets: the prolactin receptor (K D = 2.3±0.2 nM) and mouse serum albumin (K D = 0.38±0.01 nM). Further investigation showed that it could efficiently prevent prolactin mediated phosphorylation of STAT5 at 100 nM concentration and above, similar to the PrlRA itself, suggesting a potential as drug for cancer therapy in the future. Complexion with HSA weakened the affinity for the receptor to 21±3 nM, however the ability to prevent phosphorylation of STAT5 was still prominent. Injection into rats showed a 100-fold higher concentration in blood after 24 h compared to PrlRA itself.

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“…Moreover, affibody structure permits site-specific conjugation of a payload for the development of targeted therapeutic agents with well-defined pharmacokinetics. We have recently demonstrated that affibody molecules could be successfully used as targeting vehicles for the delivery of a cytotoxic drug for cancer therapy [10].…”

Section: Introductionmentioning

confidence: 99%

Influence of Several Compounds and Drugs on the Renal Uptake of Radiolabeled Affibody Molecules

2020

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Affibody molecules are the most studied class of engineered scaffold proteins (ESPs) in radionuclide molecular imaging. Attempts to use affibody molecules directly labelled with radiometals for targeted radionuclide therapy were hampered by the high uptake and retention of radioactivity in kidneys. Several promising strategies have been implemented to circumvent this problem. Here, we investigated whether a pharmacological approach targeting different components of the reabsorption system could be used to lower the uptake of [99mTc]Tc-ZHER:2395 affibody molecule in kidneys. Pre-injection of probenecid, furosemide, mannitol or colchicine had no influence on activity uptake in kidneys compared to the control group. Mice pre-injected with maleate and fructose had 33% and 51% reduction in the kidney-associated activity, respectively, compared to the control group. Autoradiography images showed that the accumulation of activity after [99mTc]Tc-ZHER2:2395 injection was in the renal cortex and that both maleate and fructose could significantly reduce it. Results from this study demonstrate that pharmacological intervention with maleate and fructose was effective in reducing the kidney uptake of affibody molecules. A presumable mechanism is the disruption of ATP-mediated cellular uptake and endocytosis processes of affibody molecules by tubular cells.

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Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors

Cited by 45 publications

References 38 publications

Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer

Zein nanoparticles as nontoxic delivery system for maytansine in the treatment of non-small cell lung cancer

An in vivo half-life extended prolactin receptor antagonist can prevent STAT5 phosphorylation

Influence of Several Compounds and Drugs on the Renal Uptake of Radiolabeled Affibody Molecules

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