Second-Generation Tunable pH-Sensitive Phosphoramidate-Based Linkers for Controlled Release

Choy, Cindy J.; Ley, Corinne Rose; Davis, Austen L.; Backer, Brian S.; Geruntho, Jonathan J.; Clowers, Brian H.; Berkman, Clifford E.

doi:10.1021/acs.bioconjchem.6b00422

Cited by 38 publications

(30 citation statements)

References 37 publications

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“…They also showed potential therapeutic activities and are known as potential alternative genetic systems (Gryaznov, 1999;Chen et al, 2009). Elaborate studies have been carried out in which phosphoramidate-based linkers, which are responsive to pH, do not require intracellular enzymatic action to initiate drug release (Choy et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Exploring concomitant/conformational dimorphism in a difluoro-substituted phosphoramidate derivative

Hasija

Chopra

2019

Acta Crystallogr C

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The concomitant occurrence of dimorphs of diphenyl (3,4-difluorophenyl)phosphoramidate, C 18 H 14 F 2 NO 3 P, was observed via a solution-mediated crystallization process with variation in the symmetry-free molecules (Z 0 ). The existence of two forms, i.e. Form I (block, Z 0 = 1) and Form II (needle, Z 0 = 2), was characterized by single-crystal X-ray diffraction, differential scanning calorimetry and powder X-ray diffraction. Furthermore, a quantitative analysis of the energetics of the different intermolecular interactions was carried out via the energy decomposition method (PIXEL), which corroborates with inputs from the energy framework and looks at the topology of the various intermolecular interactions present in both forms. The unequivocally distinguished contribution of strong N-HÁ Á ÁO hydrogen bonds along with other interactions, such as C-HÁ Á ÁO, C-HÁ Á ÁF,and C-HÁ Á Á, mapped on the Hirshfeld surface is depicted by two-dimensional fingerprint plots. Apart from the major electrostatic contribution from N-HÁ Á ÁO hydrogen bonds, the crystal structures are stabilized by contributions from the dispersion energy. The closely related melting points and opposite trends in the calculated lattice energies are interesting to investigate with respect to the thermodynamic stability of the observed dimorphs. The significant variation in the torsion angles in both forms helps in classifying them in the category of conformational polymorphs.Displacement ellipsoid plots (50% probability) of (a) dimorph Form I (Z 0 = 1) and (b) dimorph Form II (Z 0 = 2). For Form II, molecule A is depicted in olive and molecule B in purple.

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Section: Introductionmentioning

confidence: 99%

Exploring concomitant/conformational dimorphism in a difluoro-substituted phosphoramidate derivative

Hasija

Chopra

2019

Acta Crystallogr C

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“…14 Currently, several studies have demonstrated that the acidic condition in the tumor site is a promising means of eliciting drug release. [15][16][17][18] And, in our work, we found that drug molecules of Pt were preferentially released from the nanodrug in acidic conditions compared with the normal physical condition.…”

Section: Introductionmentioning

confidence: 55%

Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Zheng¹,

Yin²,

Cai³

et al. 2018

IJN

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Background Tumor microenvironment plays an important role in the chemoresistance of oral squamous cell carcinoma (OSCC). Hypoxia in the microenvironment is one of the important factors that contributes to OSCC chemoresistance; therefore overcoming hypoxia-mediated chemoresistance is one of the great challenges in clinical practice. Methods In this study, we developed a drug delivery system based on Pt-loaded, polyethylene glycol-modified graphene quantum dots via chemical oxidation and covalent reaction. Results Our results show that synthesized polyethylene glycol-graphene quantum dots-Pt (GPt) is about 5 nm in diameter. GPt sensitizes OSCC cells to its treatment in both normoxia and hypoxia conditions. Inductively coupled plasma-mass spectrometry assay shows that GPt enhances Pt accumulation in cells, which leads to a notable increase of S phase cell cycle arrest and apoptosis of OSCC cells in both normoxia and hypoxic conditions. Finally, compared with free cisplatin, GPt exhibits a strong inhibitory effect on the tumor growth with less systemic drug toxicity in an OSCC xenograft mouse tumor model. Conclusion Taken together, our results show that GPt demonstrates superiority in combating hypoxia-induced chemoresistance. It might serve as a novel strategy for future microenvironment-targeted cancer therapy.

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“…As anticipated, the rate of P−N bond hydrolysis of the payload-phosphoramidate system 1−3 followed pseudo-firstorder kinetics at all pH values (Figure 2B), consistent with our initial studies. 44,47,48 The rate constants (k 1 ) are summarized in Table 1. Importantly, there was no detectable hydrolysis observed for the modules at physiological pH (Figure 2C−E).…”

Section: Resultsmentioning

confidence: 99%

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

et al. 2021

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The tunable nature of phosphoramidate linkers enables broad applicability as pH-triggered controlled-release platforms, particularly in the context of antibody- and small-molecule-drug conjugates (ADCs and SMDCs), where there remains a need for new linker technology. Herein, we explored in-depth the release of turn-on fluorogenic payloads from a homoserinyl-based phosphoramidate acid-cleavable linker. Kinetics of payload release from the scaffold was observed in buffers representing the pH conditions of systemic circulation, early and late endosomes, and lysosomes. It was found that payload release takes place in two key consecutive steps: (1) P–N bond hydrolysis and (2) spacer immolation. These two steps were found to follow pseudo-first-order kinetics and had opposite dependencies on pH. P–N bond hydrolysis increased with decreasing pH, while spacer immolation was most rapid at physiological pH. Despite the contrasting release kinetics of these two steps, maximal payload release was observed at the mildly acidic pH (5.0–5.5), while minimal payload release occurred at physiological pH. We integrated this phosphoramidate-payload linker system into a PSMA-targeted fluorescent turn-on probe to study the intracellular trafficking and release of a fluorescent payload in PSMA-expressing prostate cancer cells. Results showed excellent turn-on and accumulation of the coumarin payload in the late endosomal and lysosomal compartments of these cells. The release properties of this linker mark it as an attractive alternative in the modular design of ADCs and SMDCs, which demand selective intracellular payload release triggered by the pH changes that accompany intracellular trafficking.

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Second-Generation Tunable pH-Sensitive Phosphoramidate-Based Linkers for Controlled Release

Cited by 38 publications

References 37 publications

Exploring concomitant/conformational dimorphism in a difluoro-substituted phosphoramidate derivative

Exploring concomitant/conformational dimorphism in a difluoro-substituted phosphoramidate derivative

Antitumor effect of a Pt-loaded nanocomposite based on graphene quantum dots combats hypoxia-induced chemoresistance of oral squamous cell carcinoma

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells

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