A pH-responsive crosslinker platform for antibody-drug conjugate (ADC) targeting delivery

Migliorini, Francesca; Cini, Elena; Dreassi, Elena; Finetti, Federica; Ievoli, Giovanni; Macrì, Giulia; Petricci, Elena; Rango, Enrico; Trabalzini, Lorenza; Taddei, Maurizio

doi:10.1039/d2cc03052g

Cited by 11 publications

(13 citation statements)

References 36 publications

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“…Therefore, we decided to form the activated carbonate from benzyl alcohol 11 ( Scheme 3 ). This linker, which is based on orthoester chemistry, was derived from gallic acid and is known to undergo the uncage process at a pH of 5.5 [ 31 ]. Carbonylation of 11 was carried out as previously described for compound 4 , and the activated carbonate 12 was used for the acylation of Linezolid 7 , Enzalutamide 9 , and Tasimelteon 13 , a drug developed for sleep disorders [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

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A Self-Immolative Linker for the pH-Responsive Release of Amides

et al. 2023

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The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h.

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Section: Resultsmentioning

confidence: 99%

“…General procedure for release experiments [ 31 ]. A 10 mM stock-solution of compounds 8a , 8b , 10 , 15 , 17 , and 18 was prepared in DMSO and diluted in the corresponding buffers to obtain a 1 mM solution.…”

Section: Methodsmentioning

confidence: 99%

A Self-Immolative Linker for the pH-Responsive Release of Amides

et al. 2023

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“…The release experiments were performed in pH 7.4 and pH 5.5 PBS to simulate the normal physiological environment and acidic tumor environment, respectively (Liu et al., 2022 ; Migliorini et al., 2022 ). In our study, PEI and DOX were connected by a hydrazone bond, which was easily broken under acidic conditions, resulting in pH sensitivity of PEI-DOX/EGCG/FA.…”

Section: Resultsmentioning

confidence: 99%

Enhanced therapeutic efficacy of doxorubicin against multidrug-resistant breast cancer with reduced cardiotoxicity

Zhang

Wang

et al. 2023

Drug Delivery

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Doxorubicin (DOX), a commonly used anti-cancer drug, is limited by its cardiotoxicity and multidrug resistance (MDR) of tumor cells. Epigallocatechin gallate (EGCG), a natural antioxidant component, can effectively reduce the cardiotoxicity of DOX. Meanwhile, EGCG can inhibit the expression of P-glycoprotein (P-gp) and reverse the MDR of tumor cells. In this study, DOX is connected with low molecular weight polyethyleneimine (PEI) via hydrazone bond to get the pH-sensitive PEI-DOX, which is then combined with EGCG to prevent the cardiotoxicity of DOX and reverse the MDR of cancer cells. In addition, folic acid (FA) modified polyethylene glycol (PEG) (PEG-FA) is added to get the targeted system PEI-DOX/EGCG/FA. The MDR reversal and targeting ability of PEI-DOX/EGCG/FA is performed by cytotoxicity and in vivo anti-tumor activity on multidrug resistant MCF-7 cells (MCF-7/ADR). Additionally, we investigate the anti-drug resistant mechanism by Western Blot. The ability of EGCG to reduce DOX cardiotoxicity is confirmed by cardiotoxicity assay. In conclusion, PEI-DOX/EGCG/FA can inhibit the expression of P-gp and reverse the MDR in tumor cells. It also shows the ability of remove oxygen free radicals effectively to prevent the cardiotoxicity of DOX.

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“…Components of ADCs and different linkers including (a) noncleavable, (b) chemically cleavable, and (c) enzymatically cleavable (enzymes inside the lysosome) linkers that have been developed to covalently link the antibody and the payload. ,− PBD, pyrrolobenzodiazepine; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin F.…”

Section: How Are Antibodies Used?mentioning

confidence: 99%

“…This design greatly improved the stability of ADCs with a half-life of more than 7 days in human plasma and should be sufficient to sustain the integrity of acid-cleavable ADCs with highly cytotoxic payloads. Later, Taddei and co-workers reported a new 1–6 self-immolative, traceless cross-linker derived from gallic acid, 5-(hydroxymethyl) pyrogallol orthoester derivative (HMPO), for the conjugation of ADCs . The resulting ADCs were stable for 24 h at pH 7.4 and 6.6 while showing acid-dependent cleavage at pH 5.5, promising for targeted release of toxic drugs inside cancer cells.…”

Section: How Are Antibodies Used?mentioning

confidence: 99%

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

et al. 2023

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The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more “undruggable” targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

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A pH-responsive crosslinker platform for antibody-drug conjugate (ADC) targeting delivery

Abstract: Gallic acid, a key component of red wine tannins, has been transformed into a linker that releases Doxorubicine or Combretastatin A4 at pH 5.5 in cancer cells.

Cited by 11 publications

References 36 publications

A Self-Immolative Linker for the pH-Responsive Release of Amides

A Self-Immolative Linker for the pH-Responsive Release of Amides

Enhanced therapeutic efficacy of doxorubicin against multidrug-resistant breast cancer with reduced cardiotoxicity

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

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