Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy

Yan, Chong; Liu, Jiyong; Wu, Xin; Tai, Zongguang; Gao, Yuan; Zhu, Quangang; Li, Jiafei; Zhang, Lijuan; Hu, Chuling; Gu, Fenfen; Gao, Jing; Gao, Shen

doi:10.1016/j.jconrel.2016.04.034

Cited by 90 publications

(64 citation statements)

References 58 publications

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“…Kojima et al reported that miR-34a reversed PTX resistance by targeting the downstream genes including SIRT1 and Bcl-2 (7). Yao et al reported that combination therapy using doxorubicin and miR-34a synergistically enhanced the antitumor property of doxorubicin and inhibited DU145 cell formed tumor growth in vivo (8). Nonetheless, intrinsic challenges associated with oligonucleotide-based miRNA replenishment including off-target effects, poor cellular uptake, and in vivo instability hindered its clinical translation.…”

Section: Introductionmentioning

confidence: 99%

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

et al. 2017

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Treatment of prostate cancer with paclitaxel (PTX) often fails due to development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that co-delivery of PTX and 2′-hydroxy-2,4,4′,5,6′-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes PTX-resistant prostate cancer cells, killing both cancer stem-like cells (CSCs) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. PTX and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70 ± 0.10% and 5.34 ± 0.02% for PTX and rubone, respectively, controlling a drug release of 60.20 ± 2.67% and 60.62 ± 4.35% release of PTX and rubone at 24 h. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing PTX concentration. Co-incubation with a miR-34a inhibitor diminished the effect of rubone. PTX IC50 in PC3 and PC3-TXR cells was 55.6 and 2580 nM, respectively, but decreased to 49.8 and 93.2 nM when treated in combination with rubone, demonstrating a reversal of PTX resistance by rubone. Systemic administration of micelles carrying PTX and rubone inhibited orthotopic prostate tumor growth in nude mice, compared to monotherapy, by reversing the expression of miR-34a, SIRT1, Cyclin D1 and E-cadherin. In summary, our results showed how rubone acts as an efficient small molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of PTX in PTX-resistant prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

et al. 2017

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“…First experiments in which miR-15a, miR-16-1 [168], miR-34a [169], miR-124 [170] or miR-145 [171] were delivered into prostate tumor cells showed a reduction of proliferation. Importantly, intravenous miR-124 treatment of mice bearing a CWR22 xenograft results in significant tumor growth inhibition.…”

Section: Suppressor Micrornas As Potential Treatment For Prostate mentioning

confidence: 99%

Exploiting Epigenetic Alterations in Prostate Cancer

Baumgart

Haendler

2017

IJMS

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Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.

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“…It is a significant challenge to develop delivery systems for drug/nucleic acid combinations, due to the physicochemical differences between the two agents. Among the available delivery systems, biodegradable polymeric nanoparticles have been the most successful delivery platforms used in drug/nucleic acid combinations [8–10]. Polymeric nanoparticles are typically composed of pharmacologically inert polymer suitable for encapsulation of both types of therapeutic cargos [11].…”

Section: Introductionmentioning

confidence: 99%

Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy

Xie

Murray-Stewart

Wang

et al. 2017

Journal of Controlled Release

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Combination of anticancer drugs with therapeutic miRNA has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.

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Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy

Cited by 90 publications

References 58 publications

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

Exploiting Epigenetic Alterations in Prostate Cancer

Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy

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