Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate

Mollaev, M. D.; Gorokhovets, Neonila V.; Nikolskaya, Elena; Faustova, M. O.; Zabolotskii, Artur; Жунина, О. А.; Sokół, Maria; Замулаева, И. А.; Северин, Е. С.; Yabbarov, N. G.

doi:10.1016/j.ijpharm.2018.12.073

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…107 The same anhydride was successfully used to link curcumin to pluronic F68 micelles. 108 It was also used to link doxorubicin to target alpha-fetoprotein receptor 109 and to chitosan nanoparticles, 110 as well as to PEI nanoparticles for the codelivery of siRNA, 111 or even for the formation of multilayer films with oxidized alginate as a nonvascular stent coating to ensure bactericidal and long-term release properties. 112 A magnetic version of chitosan nanoparticles was also studied.…”

Section: -Cis-aconitic Anhydridementioning

confidence: 99%

Cyclic Anhydrides as Powerful Tools for Bioconjugation and Smart Delivery

Spanedda

Bourel-Bonnet

2021

Bioconjugate Chem.

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Cyclic anhydrides are potent tools for bioconjugation, therefore they are broadly used in the functionalization of biomolecules and carriers. The pH-dependent stability and reactivity, as well as the physical properties, can be tuned by the structure of the cyclic anhydride used, thus their application in smart delivery systems has become very important. This review intends to cover the last updates in the use of cyclic anhydrides as pH-sensitive linkers, their differences in reactivity and the latest applications found in bioconjugation chemistry, or chemical biology and when possible, in drug delivery.

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Section: -Cis-aconitic Anhydridementioning

confidence: 99%

Cyclic Anhydrides as Powerful Tools for Bioconjugation and Smart Delivery

Spanedda

Bourel-Bonnet

2021

Bioconjugate Chem.

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“…Unfortunately, passive targeting via enhanced permeability and retention effect (EPR) is often insufficient, so researchers additionally apply various targeting ligands to ensure a sufficient accumulation and antitumor effect, such as antibodies, growth factors, transferrin, alpha-fetoprotein, cytokines, folic acid, low-density lipoprotein, tumor proteases, and tumor matrix proteins [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe

Yabbarov

Nikolskaya

Sokół

et al. 2022

IJMS

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The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety—alpha-fetoprotein receptor-binding peptide—enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.

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“…AFP is known to selectively bind and to be internalized by a wide range of cancer cells. Different researchers reported its suitability for anticancer drug delivery systems as targeting motif [18][19][20][21]. Recent studies showed that endogenous full-length AFP may promote hepatic cancer progression and is not recommended for human treatment; however, the mechanism is not completely understood [22,23].…”

Section: Introductionmentioning

confidence: 99%

Expression of acid cleavable Asp-Pro linked multimeric AFP peptide in E. coli

Mollaev

Zabolotskii

Gorokhovets

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Difficult to express peptides are usually produced by co-expression with fusion partners. In this case, a significant mass part of the recombinant product falls on the subsequently removed fusion partner. On the other hand, multimerization of peptides is known to improve its proteolytic stability in E. coli due to the inclusion of body formation, which is sequence specific. Thereby, the peptide itself may serve as a fusion partner and one may produce more than one mole of the desired product per mole of fusion protein. This paper proposes a method for multimeric production of a human alpha-fetoprotein fragment with optimized multimer design and processing. This fragment may further find its application in the cytotoxic drug delivery field or as an inhibitor of endogenous alpha-fetoprotein. Results Multimerization of the extended alpha-fetoprotein receptor-binding peptide improved its stability in E. coli, and pentamer was found to be the largest stable with the highest expression level. As high as 10 aspartate-proline bonds used to separate peptide repeats were easily hydrolyzed in optimized formic acid-based conditions with 100% multimer conversion. The major product was represented by unaltered functional alpha-fetoprotein fragment while most side-products were its formyl-Pro, formyl-Tyr, and formyl-Lys derivatives. Single-step semi-preparative RP-HPLC was enough to separate unaltered peptide from the hydrolysis mixture. Conclusions A recombinant peptide derived from human alpha-fetoprotein can be produced via multimerization with subsequent formic acid hydrolysis and RP-HPLC purification. The reported procedure is characterized by the lower reagent cost in comparison with enzymatic hydrolysis of peptide fusions and solid-phase synthesis. This method may be adopted for different peptide expression, especially with low amino and hydroxy side chain content.

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Type of pH sensitive linker reveals different time-dependent intracellular localization, in vitro and in vivo efficiency in alpha-fetoprotein receptor targeted doxorubicin conjugate

Cited by 17 publications

References 31 publications

Cyclic Anhydrides as Powerful Tools for Bioconjugation and Smart Delivery

Cyclic Anhydrides as Powerful Tools for Bioconjugation and Smart Delivery

Synergetic Enhancement of Tumor Double-Targeted MRI Nano-Probe

Expression of acid cleavable Asp-Pro linked multimeric AFP peptide in E. coli

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