Reversing the undesirable pH-profile of doxorubicin <i>via</i> activation of a di-substituted maleamic acid prodrug at tumor acidity

Zhang, Anqi; Yao, Lan; An, Ming

doi:10.1039/c7cc06843c

Cited by 19 publications

(29 citation statements)

References 28 publications

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“…The release mechanism of the maleic amide linker remains speculative. Zhang et al 55 be the key step that gave this unique hydrolysis profile of the maleamic acid derivatives (including phthalamic amide). The pH dependence of the reaction indicates there is a component of specific-acid catalysis.…”

Section: Maleic Acid-derived Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites. K E Y W O R D S antibody-drug conjugates, click and release, drug delivery, linker chemistry, targeted delivery, triggered release 1 | INTRODUCTION In the world of drug discovery and development, the concept of "smart drugs" broadly refers to those that can selectively affect disease-relevant target(s). However, to a certain degree, essentially all drugs are already selective toward the desired target(s) whether they are enzyme inhibitors, receptor ligands, ion channel blockers, inhibitors of protein-protein interaction, or even genotoxins used for cancer chemotherapy, among others. They would not have made through the various milestones of drug discovery and developmental processes if they were not sufficiently selective for the intended target(s). However, once administered into the human body, the highly complex living system often leads to many unexpected off-target effects. Thus, various additional approaches have been studied and

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Section: Maleic Acid-derived Linkersmentioning

confidence: 99%

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Yang

Pan

Choudhury

et al. 2020

Medicinal Research Reviews

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“…B) Molecular structure of doxorubicin prodrug 18 featuring a disubstituted maleamic acid trigger and the hydrophilic glutathione (GSH) tag. While mildly acidic conditions promote drug release, hydrolysis at neutral pH competes with formation of stable imide 19 …”

Section: Exploiting the Hallmarks Of Cancer: Linker Cleavage Promotedmentioning

confidence: 99%

“…For instance, An and co‐workers recently developed a doxorubicin prodrug ( 18 ) endowed with a disubstituted maleamic acid trigger. The group showed that the equilibrium with the imide form 19 at neutral pH can inhibit doxorubicin release, whereas the fast hydrolytic cleavage results in efficient and selective drug release even at mildly acidic pH (6.5–6.9) …”

Section: Exploiting the Hallmarks Of Cancer: Linker Cleavage Promotedmentioning

confidence: 99%

“…While mildly acidic conditions promotedrug release, hydrolysisat neutral pH competes with formationo fs table imide 19. [63] thracycline agents have been prepared through the installation of a cis-aconityl linker at the daunosamine moiety. [61] Recently,t he substituent effects on the hydrolysis rates at differentp Hv alues of maleamic acid derivatives were investigated by NMR studies.…”

Section: Hydrolytically Labile Linkersmentioning

confidence: 99%

“…For instance, An and co-workers recently developed ad oxorubicin prodrug (18)e ndowed with ad isubstitutedm aleamic acid trigger.T he group showed that the equilibrium with the imide form 19 at neutralp Hc an inhibit doxorubicin release, whereas the fast hydrolytic cleavage results in efficient and selective drug releasee ven at mildly acidic pH (6.5-6.9). [63] Proximal functional groups can also promote the releaseo f amine cargoes in phosphoramidate derivatives( Scheme 4A). In particular,B erkman and co-workersr ecently reported that the introduction of Hb ond donors (e.g.…”

Section: Hydrolytically Labile Linkersmentioning

confidence: 99%

See 2 more Smart Citations

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

Corso

Pignataro

Belvisi

et al. 2019

Chemistry A European J

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The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well‐known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions).

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Liposomes with Water as a pH‐Responsive Functionality for Targeting of Acidic Tumor and Infection Sites

et al. 2021

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Al ipid named DCPAw as synthesized under microwave-assisted heating. DCPAp ossesses ap yridine betaine,h ydrophilic group that can be complexed with water through hydrogen bonding (DCPA-H 2 O). DCPA-H 2 Ol iposomes became protonated relatively fast already at pH < 6.8, due to the high HOMO binding energy of DCPA-H 2 O. In murine models,D CPA-H 2 Ol iposomes had longer blood circulation times than natural DPPC or cationic DCPM liposomes,w hile after tail-vein injection DCPA-H 2 Ol iposomes targeted faster to solid tumors and intra-abdominal infectious biofilms.T herapeutic efficacy in am urine,i nfected wound-healing model of tail-vein injected ciprofloxacin-loaded DCPA-H 2 Ol iposomes exceeded the ones of clinically applied ciprofloxacin as well as of ciprofloxacin-loaded DPPC or DCPM liposomes.

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Reversing the undesirable pH-profile of doxorubicin via activation of a di-substituted maleamic acid prodrug at tumor acidity

Cited by 19 publications

References 28 publications

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

Liposomes with Water as a pH‐Responsive Functionality for Targeting of Acidic Tumor and Infection Sites

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