Inhibition of Cancer Cell Proliferation and Breast Tumor Targeting of pHLIP–Monomethyl Auristatin E Conjugates

Burns, Kelly E.; Robinson, Matthew K.; Thévenin, Damien

doi:10.1021/mp500779k

Cited by 58 publications

(86 citation statements)

References 46 publications

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“…pHLIP therefore appears to improve MMAF potency at lower pH by facilitating its translocation across the cell membrane in a mechanism more favorable than passive diffusion. Similar to our previous study with pHLIP–MMAE conjugates, 12,15–18 pHLIP(D25E)–MMAF shows less potency than the pHLIP(WT) conjugate with an IC 50 at pH 5.0 of 368 nM. It also displays the smallest pH selectivity of all conjugates, with less than 3-fold improvement at low pH over physiological pH.…”

Section: Resultssupporting

confidence: 84%

“…12 Advantageously when compared to other type of targeting and delivering methods, the properties of small peptides can be adjusted relatively easily by modifying their amino acid sequence. The pHLIP peptides shown in Table 1 have been chosen to cover a wide range of properties with the objective to tune/improve selectivity and translocation in cultured cells and tumor localization in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Apart from our own work with pHLIP(WT)–MMAE, pHL P-(D14Gla;D25Aad) has been shown in conjugation with taxol against A549 cultured cells but with marginal effect, and pHLIP(WT) in conjugation with a peptide nucleic acid showed promising therapeutic efficacy in mice. 10–12 …”

Section: Resultsmentioning

confidence: 99%

“…It is consistent with our previous observation that the disulfide bond between pHLIP and MMAE is stable in cell media over the time frame of the cell treatment. 12,21 …”

Section: Resultsmentioning

confidence: 99%

“…7–14 We recently showed that pHLIP provides localized delivery of monomethyl auristatin E (MMAE) to cancer cells. 12 This previous study shows that pHLIP-mediated translocation of MMAE inhibits the proliferation of cancer cells in a pH-selective and concentration-dependent fashion and that it offers clear advantages over treatment with free MMAE. The same study also shows that the pHLIP–MMAE conjugate effectively targets triple-negative breast tumor xenografts in mice and that pHLIP–MMAE is stable in serum over a relevant time frame for its systemic clearance rate.…”

Section: Introductionmentioning

confidence: 92%

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Therapeutic Efficacy of a Family of pHLIP–MMAF Conjugates in Cancer Cells and Mouse Models

et al. 2017

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The targeting of therapeutics specifically to diseased tissue is crucial for the development of successful cancer treatments. The approach here is based on the pH(low) insertion peptide (pHLIP) for the delivery of a potent mitotic inhibitor monomethyl auristatin F (MMAF). We investigated six pHLIP variants conjugated to MMAF to compare their efficacy in vitro against cultured cancer cells. While all pHLIP–MMAF conjugates exhibit potent pH- and concentration-dependent killing, their cytotoxicity profiles are remarkably different. We also show that the lead conjugate exhibits significant therapeutic efficacy in mouse models without overt toxicities. This study confirms pHLIP–monomethyl auristatin conjugates as possible new therapeutic options for cancer treatment and supports their further development.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…It is consistent with our previous observation that the disulfide bond between pHLIP and MMAE is stable in cell media over the time frame of the cell treatment. 12,21 …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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Therapeutic Efficacy of a Family of pHLIP–MMAF Conjugates in Cancer Cells and Mouse Models

et al. 2017

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Peptide Targeting Methods

Patil

et al. 2019

Handbook of in Vivo Chemistry in Mice

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Protonation‐Driven Membrane Insertion of a pH‐Low Insertion Peptide

et al. 2016

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The pH-lowi nsertion peptide (pHLIP) inserts into membranes and forms at ransmembrane (TM) a-helix in response to slight acidity,a nd has shown great potential for cancer diagnosis and treatment. As alead, pHLIP is challenging to optimize because the mechanism of its pH-dependent membrane interactions is not completely understood. Within pHLIP there are multiple D/E residues which could sense the pH change,t he particular role played by eacho ft hem in the protonation-driven insertion process is not clear.T he precise location of the TM helix within the pHLIP sequence is also unknown. In this work, solid-state NMR spectroscopyi su sed to address these central questions.T racing backbone conformations revealed that the TM helix spans from A10 to D33 with abreak at T19 to P20. Residue-specific pK a values of D31, D33, D25, and D14 were determined to be 6.5, 6.3, 6.1, and 5.8, respectively,a nd define the sequence of protonations which lead to insertion. Furthermore,p ossible intermediate states which disrupt membranes at pH 6.4 were proposed based on tryptophan fluorescence quenching and NMR data.The 36-residue (GGEQNPIYWARYA DWLFTTPLLLL-DLALLVDADEGT) pH-low insertion peptide (pHLIP), which is extracted from the bacteriorhodopsin helix C, can sense microenvironmental pH change and inserts into lipid bilayers as atransmembrane (TM) a-helix below acritical pH value. [1][2][3][4][5][6] Thepeptide is largely unfolded in aqueous solution (state I) and on the membrane surface (state II), and forms the folded state III upon insertion. [4] Biomedical applications of pHLIP (and its analogues) have attracted increasing attentions because of their controllable responses to slight acidity in the pH range of 6-7 found in various diseased states. They have been utilized as imaging tools and diagnostic agents for cancer, inflammation, and ischaemic myocardium. [1,4,5,[7][8][9][10] Furthermore,p HLIP technology constitutes an ew,p H-responsive,c ross-membrane cytoplasmic cargo delivery platform. Avariety of molecules,i ncluding fluorescent dyes,cytotoxins,chemotherapy drugs,and biomolecules, such as peptide nucleic acids (PNA), have been delivered into cells using pHLIP. [11][12][13][14][15][16][17][18][19][20] To extend the biomedical applications of pHLIP to broader systems with higher efficiency,a ppropriate tuning of its primary sequence is necessary, [21,22] and to do so requires an in-depth and detailed understanding of its pH-regulated membrane insertion process,which is currently not available.Them acroscopic, apparent pH 50 ,d efined as the pH at which 50 %o ft he pHLIP molecules are inserted (also referred to as pK or pK a of insertion by others), has been estimated to be about 6.1-6.2 by following fluorescence changes of Wresidues at positions 9and 15. [1,4] However,this assay is indirect and it is not clear which protonations of the D/E side chains within the pHLIP sequence correlate with aWfluorescence blue-shift and an increase of fluorescence intensity.The original hypothesis of how pH regulates pHLIP insertion rest...

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Inhibition of Cancer Cell Proliferation and Breast Tumor Targeting of pHLIP–Monomethyl Auristatin E Conjugates

Cited by 58 publications

References 46 publications

Therapeutic Efficacy of a Family of pHLIP–MMAF Conjugates in Cancer Cells and Mouse Models

Therapeutic Efficacy of a Family of pHLIP–MMAF Conjugates in Cancer Cells and Mouse Models

Peptide Targeting Methods

Protonation‐Driven Membrane Insertion of a pH‐Low Insertion Peptide

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