Supramolecularly enabled pH- triggered drug action at tumor microenvironment potentiates nanomedicine efficacy against glioblastoma

Quader, Sabina; Liu, Xueying; Toh, Kazuko; Su, Yu‐Lin; Maity, Amit Ranjan; Tao, Anqi; Paraiso, West Kristian D.; Mochida, Yuki; Kinoh, Hiroaki; Cabral, Horacio; Kataoka, Kazunori

doi:10.1016/j.biomaterials.2020.120463

Cited by 44 publications

(26 citation statements)

References 36 publications

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“…The drug release rate of the micelles was studied at different pH levels, ranging from pH 7.4 to pH 3.0 (Figure e and SI Figure S4). The micelles prepared with the aliphatic linker released JQ1H rapidly at intratumoral pH 6.5 (Figure e) and further accelerated the discharge of JQ1H in the pH range between 4.5 and 6.5, which is the pH of late endosomes and lysosomes inside the cells. − Conversely, the micelles prepared with the aromatic linker released JQ1H at a much slower rate at intratumoral pH 6.5 and late endosome/lysosome pH 4.5–6.5. Thus, we referred to the pH-sensitive micelles made with the aliphatic linker as fast-release JQ1H-loaded micelles (FR-JQ1H/m) and the pH-sensitive micelles made with the aromatic linker as slow-release JQ1H-loaded micelles (SR-JQ1H/m).…”

Section: Resultsmentioning

confidence: 94%

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile

et al. 2021

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Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.

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Section: Resultsmentioning

confidence: 94%

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile

et al. 2021

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“…At pH 6.5, SCC-NPs gradually became positively charged after h, suggesting the recovery of aminomethyl phenylalanine moieties for sustained release of the drugs. [45][46][47] While SCC-NPs at pH 7.4 and Ctr-NPs at pH 6.5 and 7.4 remained negatively charged. The stability of SCC-NPs at pH 7.4 would effectively restrain the drug release in normal tissues.…”

Section: Resultsmentioning

confidence: 95%

Self-Motivated Supramolecular Combination Chemotherapy for Overcoming Drug Resistance Based on Acid-Activated Competition of Host–Guest Interactions

Wang

et al. 2021

CCS Chem

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In this work, we proposed a nanoparticle-based strategy of self-motivated supramolecular combination chemotherapy that carried drugs stably and released drugs actively under the acidic tumor microenvironment to overcome the drug resistance of cancer cells. This self-motivated nanoparticle consisted of a cucurbit[7]urilcontaining polymer (PCB)-based core, in which the oxaliplatin and a mitochondria-targeting cytotoxic peptide with an N-terminal phenylalanine were stably loaded through host-guest interactions, and a polymeric protection shell containing acid-activated competitors for releasing drugs. In the acidic tumor environment, the protected aminomethyl phenylalanine moieties on the polymer shell were recovered with a remarkably increase in the binding constant toward cucurbit[7]uril, which competitively replaced and released the combination drugs in PCB. With the synergistic effect of released mitochondria-targeting cytotoxic peptides that effectively inhibited the energy-dependent drug efflux, this self-motivated nanoparticle augmented the anticancer activity of oxaliplatin against drug-resistant cells. This strategy of self-motivated supramolecular combination chemotherapy provides a new method for efficient combination of chemical drugs and bioactive peptides with on-demand drug release, and opens a great prospect of supramolecular chemotherapy toward overcoming the drug resistance of cancers.

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“…A change with the composition and concentration of solution buffer can result in a fluctuation in the dielectric permittivity of medium, and thus change the magnitude of van der Waals interactions. Such efforts on environment‐dependence of interpeptide interactions should be rigorously pursued in future efforts for developing peptide‐enabled delivery systems towards tumor microenvironments 35–37 …”

Section: Resultsmentioning

confidence: 99%

Composition‐dependent multivalency of peptide–peptide interactions revealed by tryptophan‐scanning mutagenesis

Zheng

Fang

et al. 2021

Journal of Peptide Science

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We have examined in this contribution the composition dependence of binding characteristics in peptide–peptide interactions between an oligopeptide octa‐glycine and a series of tryptophan‐containing octapeptides. The binding energy associated with tryptophan–glycine interactions manifests pronounced stepwise binding characteristics as the number of tryptophan increases from 0 to 8 in the octapeptides consisting only of glycine and can be attributed to mono‐, di‐, and tri‐valent peptide–peptide interactions. At the same time, only weak fluctuations in binding energy were observed as the number of tryptophan increases from 2 to 7. Such distinctive nonlinearity of composition‐dependent tryptophan–glycine binding energy characteristics due to continuously varying tryptophan compositions in the octapeptides could be considered as a reflection of combinatorial contributions due to the hydrogen bonds originated from the indole moieties of tryptophan with the main chains of octapeptide of glycine containing N–H and C=O moieties and the van der Waals interactions (including π–π and π–CH interactions) between peptides.

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Supramolecularly enabled pH- triggered drug action at tumor microenvironment potentiates nanomedicine efficacy against glioblastoma

Cited by 44 publications

References 36 publications

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile

Self-Motivated Supramolecular Combination Chemotherapy for Overcoming Drug Resistance Based on Acid-Activated Competition of Host–Guest Interactions

Composition‐dependent multivalency of peptide–peptide interactions revealed by tryptophan‐scanning mutagenesis

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