Mitoxantrone- and Folate-TPGS2k Conjugate Hybrid Micellar Aggregates To Circumvent Toxicity and Enhance Efficiency for Breast Cancer Therapy

Guissi, Nida El Islem; Li, Huipeng; Xu, Yurui; Semcheddine, Farouk; Chen, Minglei; Su, Zhigui; Ping, Qineng

doi:10.1021/acs.molpharmaceut.6b01009

Cited by 19 publications

(22 citation statements)

References 45 publications

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“…Similarly, previous studies using polymeric micelles or liposomes have also achieved a high MIT encapsulation efficacy, and also drug loading efficacy with reasonable stabilities and drug release behaviors. 50, 51, 52, 53…”

Section: Resultsmentioning

confidence: 99%

Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma

et al. 2018

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In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing desmoplastic melanoma.

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Section: Resultsmentioning

confidence: 99%

Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma

et al. 2018

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“…Each point was performed in triplicates. The viability percentage was assessed using the following Equation (6) [63]:Cell viability (%)=ODS−ODN ODP−ODN×100% where OD S was the absorbance of each sample well, OD N was the absorbance of negative-control wells (PBS) and OD P was the absorbance of positive-control wells (medium).…”

Section: Methodsmentioning

confidence: 99%

Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis

Chen

J.C.²,

et al. 2019

Pharmaceutics

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Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

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“…The in vitro release was performed using the dialysis bag method (molecular weight cutoff 8-12 kDa) [34,35]. A shaking speed incubator was used to performed dialysis at 37 • C with PBS 1% (w/v) Tween-80 at pH 7.4 as the release medium.…”

Section: In Vitro Drug Releasementioning

confidence: 99%

“…After 24 h post injection, the mice were euthanized, and their major organs (brain, kidney, lung, spleen, liver, heart, and tumor) were harvested for ex vivo imaging. The mean fluorescence intensity of the collected samples was also measured [35].…”

Section: Pharmacokinetic and Biodistribution Studiesmentioning

confidence: 99%

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Co-Encapsulation of Mitoxantrone and β-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia

et al. 2020

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Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.

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Mitoxantrone- and Folate-TPGS2k Conjugate Hybrid Micellar Aggregates To Circumvent Toxicity and Enhance Efficiency for Breast Cancer Therapy

Cited by 19 publications

References 45 publications

Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma

Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma

Folate Receptor-Targeting and Reactive Oxygen Species-Responsive Liposomal Formulation of Methotrexate for Treatment of Rheumatoid Arthritis

Co-Encapsulation of Mitoxantrone and β-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia

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