A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis

Mohammad, Imran Shair; He, Wei; Yin, Lifang

doi:10.1007/s11095-018-2370-0

Cited by 48 publications

(35 citation statements)

References 60 publications

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“…Our in vitro and in vivo experiments demonstrated that the HA-PNPplex treatment elevated caspase-3 level up to 6.5-fold in MCF-7 cells ( Figure 3 ) and up to 7-fold in the tumor ( Figure 6 H-I ). In addition, we recently found that upregulation of caspase 3 was able to sensitize cancer cells to chemotherapy with PTX 43 . Therefore, this exciting antitumor effect on breast cancer is ascribed to the efficient intracellular delivery of caspase 3 by HA-PNPplex and consequent synergy between caspase 3 and PTX.…”

Section: Discussionmentioning

confidence: 99%

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Xin¹,

Teng²,

Lv³

et al. 2018

Theranostics

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Protein therapeutics is playing an increasingly critical role in treatment of human diseases. However, current vectors are captured by the digestive endo-lysosomal system, which results in an extremely low fraction (<2%) of protein being released in the cytoplasm. This paper reports a drug-delivering-drug platform (HA-PNPplex, 200 nm) for potent intracellular delivery of protein and combined treatment of cancer.Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis. In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy. Protein expression was assayed by western blot. In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology.Results: HA-PNPplex delivered the functional protein, caspase 3, to cells via bypassing endo-lysosomes and raised the caspase-3 level 6.5-fold in caspase 3-deficient cells. Promoted tumor accumulation (1.5-fold) and penetration were exhibited, demonstrating a high tumor-targeting ability of HA-PNPplex. HA-PNPplex rendered a 7-fold increase in caspase 3 in tumor and allowed for a 100% tumor growth inhibition and >60% apoptosis, implying significant antitumor activities.Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment. This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small-molecule drugs and proteins. More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy.

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Section: Discussionmentioning

confidence: 99%

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Xin¹,

Teng²,

Lv³

et al. 2018

Theranostics

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“…Releasing a considerable amount of the drug in-cell in a short period would help saturate the efflux pump and, consequently, decline the efflux of the drug and compromise the drug resistance [ 30 ]. The drug state in ANSs and LPNs was different, with the former having an amorphous state and the latter possessing a crystalline form.…”

Section: Resultsmentioning

confidence: 99%

Amorphous Nanosuspensions Aggregated from Paclitaxel–Hemoglobulin Complexes with Enhanced Cytotoxicity

et al. 2018

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Amorphous nanosuspensions (ANSs) enable rapid release and improved delivery of a poorly water-soluble drug; however, their preparation is challenging. Here, using hemoglobin (Hb) as a carrier, ANSs aggregated from paclitaxel (PTX)–Hb complexes were prepared to improve delivery of the hydrophobic anti-cancer agent. An affinity study demonstrated strong interaction between Hb and PTX. Importantly, the complexes could aggregate into <300 nm ANSs with high drug loading, which acidic condition facilitated their formation. Furthermore, the ANSs possessed improved cytotoxicity against cancer cells over the crystalline nanosuspensions. Taken together, ANSs aggregated from PTX–Hb complexes were developed, which could kill cancer cells with high efficiency.

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“…The cellular apoptosis was determined by previously described method . Briefly, the A549 cells were seeded in 6‐well plate at a density of 5 × 10 5 cells/well and incubated for 24 h at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The cellular apoptosis was determined by previously described method. [17] Briefly, the A549 cells were seeded in 6-well plate at a density of 5 9 10 5 cells/ well and incubated for 24 h at 37°C. Then, cells were incubated with different concentration of compound 1 (0.1, 1, 10 lM) and incubated for 24 h. Next, for the assessment of cellular apoptosis, the treated cells were collected, washed with PBS 3-times and stained with the Annexin V-FITC and PI at room temperature for 15 min in the dark.…”

Section: Cellular Apoptosis Assaymentioning

confidence: 99%

Phloroglucinol Derivatives from the Fruits of Eucalyptus globulus and Their Cytotoxic Activities

Pham

Mohammad

et al. 2018

Chemistry & Biodiversity

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A new phloroglucinol derivative, named eucalyptin B (1), along with five related known compounds (2 - 6), was isolated from the fruits of Eucalyptus globulus. Their structures were elucidated by means of 1D- and 2D-NMR spectroscopy, with the absolute configuration of 1 determined by electronic circular dichroism (ECD) calculations. All isolated compounds (1 - 6) were evaluated for their cytotoxic activities against lung (A549), breast (4T1), and skin (B16F10) cancer cell lines. On the basis of cell viability assay, the cytotoxic activity of eucalyptin B (1) was further confirmed by apoptosis assay. Additionally, after treatment with eucalyptin B (1), the apoptosis factor proteins (Bcl2 and Bax) and caspase-3 levels in A549 cells were also determined by Western-blot analysis. By cytotoxic assay, eucalyptin B (1) exhibited potent cytotoxicity against A549 cells with an IC value of 1.51 μm and induced concentration dependent apoptosis of up to 49%. Additionally, eucalyptin B (1) inhibited 5-fold and increased 10-folds in the level of Bcl2 and Bax, respectively. Furthermore, the 11-fold increase in the level of caspase-3 confirmed eucalyptin B (1) activated caspase dependent apoptosis pathway. In conclusion, the isolated compound eucalyptin B (1) has promising cytotoxic activity in tumor cells, especially in A549.

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A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis

Cited by 48 publications

References 60 publications

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Drug-delivering-drug platform-mediated potent protein therapeutics via a non-endo-lysosomal route

Amorphous Nanosuspensions Aggregated from Paclitaxel–Hemoglobulin Complexes with Enhanced Cytotoxicity

Phloroglucinol Derivatives from the Fruits of Eucalyptus globulus and Their Cytotoxic Activities

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