Triphenylphosphonium-modified mitochondria-targeted paclitaxel nanocrystals for overcoming multidrug resistance

Han, Xue; Su, Ruijuan; Huang, Xiuqing; Wang, Yingli; Xiao, Kun; Zhou, Shuang; Liu, Hongzhuo

doi:10.1016/j.ajps.2018.06.006

Cited by 36 publications

(19 citation statements)

References 41 publications

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“…Ultimately, this may allow cancer cells to be discriminated according to their degree of aggressiveness. The conjugation of TPP with various bioactive compounds [19,29,30] or nanocrystals [36] gives chimeric molecules an increased cellular accessibility and enhances their cytotoxicity against tumor cells. For this reason, TPP conjugates with paclitaxel [37] and doxorubicin [38] have recently been suggested to treat drug-resistant cancers.…”

Section: Introductionmentioning

confidence: 99%

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

et al. 2021

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In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

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Section: Introductionmentioning

confidence: 99%

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

et al. 2021

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“…Despite recent treatment advances, multidrug resistance (MDR) remains a major challenge in lung cancer treatment [ 2 ]. MDR is caused by multiple factors and is mediated by various intrinsic and acquired mechanisms [ 3 ]. Mitochondria are the power source of the cells, play an important role in energy generation, apoptosis, signal transduction, cell cycle, and cell differentiation, and are closely related to carcinogenesis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Selective delivery of a drug to the mitochondria can be achieved by mitochondria-targeting signal peptides [ 15 ], oligoguanidinium [ 16 ], and triphenylphosphonium (TPP) [ 17 ] to modify drug carriers in the drug delivery systems. TPP is often used in delocalized lipophilic cations, which are usually modified on the surface of nanomicelles or covalently linked with nanocarriers to achieve mitochondrial targeting [ 3 ]. Our previous study demonstrated that TPP-modified pluronic F127 (PF127), which was decorated by hyaluronic acid (HA) as a vector (TPP-PF127-HA), was able to transfer PTX to the mitochondria and disrupt their function [ 18 ]; however, PF127 has a high hydrophilic-lipophilic balance and does not significantly reverse MDR in cancer cells [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

et al. 2021

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Background Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. Results Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. Conclusions These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. Graphic Abstarct

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“…Han et al. reported that TPP + ‐modified paclitaxel exhibits better penetration and more potent inhibition than non‐targeted paclitaxel [42] . Yu et al.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Targeting Strategy for Enhanced Photothermal Cancer Therapy

et al. 2021

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Photothermal therapy (PTT) is a light‐triggered therapeutic method showing great promise in cancer treatment. For safe and effective PTT, minimal invasion and high specificity are needed. Mitochondria have been recognized as an attractive target to enhance the therapeutic efficacy of cancer treatment. Here, we present a unique type of CaCO3‐encapsulated Bi2S3 nanorods (Bi2S3@CaCO3 NRs) for improving PTT therapeutic efficacy based on a novel mitochondria‐targeted strategy. Such NRs with Bi2S3 NRs as the photothermal agent, carboxylated short‐chain PEG as bridging group and CaCO3 as pH responsive surface coating showed not only remarkable promotion of cancer uptake efficiency, but also enhanced mitochondria targeting ability. The significant improvement of phototherapeutic efficacy of Bi2S3@CaCO3 suggests that our mitochondria‐targeting strategy is a reliable and useful method for efficient cancer therapy.

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Triphenylphosphonium-modified mitochondria-targeted paclitaxel nanocrystals for overcoming multidrug resistance

Cited by 36 publications

References 41 publications

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

Mitochondrial Targeting Strategy for Enhanced Photothermal Cancer Therapy

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