Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells

Arora, Hans; Jensen, Mark P.; Yuan, Ye; Wu, Aiguo; Vogt, Stefan; Paunesku, Tatjana; Woloschak, Gayle E.

doi:10.1158/0008-5472.can-11-2890

Cited by 104 publications

(118 citation statements)

References 47 publications

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“…5F). The findings here collectively suggest that free DOX are taken up by cells by passive diffusion through the cell membrane (33), whereas FTn/FTn-PEG 2k /DOX are endocytosed, release DOX in lysosomes, and subsequently the released drug molecules diffuse into cell nuclei.…”

Section: Resultsmentioning

confidence: 57%

Protein nanocages that penetrate airway mucus and tumor tissue

Chisholm

Zhuang

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

100

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Reports on drug delivery systems capable of overcoming multiple biological barriers are rare. We introduce a nanoparticle-based drug delivery technology capable of rapidly penetrating both lung tumor tissue and the mucus layer that protects airway tissues from nanoscale objects. Specifically, human ferritin heavy-chain nanocages (FTn) were functionalized with polyethylene glycol (PEG) in a unique manner that allows robust control over PEG location (nanoparticle surface only) and surface density. We varied PEG surface density and molecular weight to discover PEGylated FTn that rapidly penetrated both mucus barriers and tumor tissues in vitro and in vivo. Upon inhalation in mice, PEGylated FTn with optimized PEGylation rapidly penetrated the mucus gel layer and thus provided a uniform distribution throughout the airways. Subsequently, PEGylated FTn preferentially penetrated and distributed within orthotopic lung tumor tissue, and selectively entered cancer cells, in a transferrin receptor 1-dependent manner, which is up-regulated in most cancers. To test the potential therapeutic benefits, doxorubicin (DOX) was conjugated to PEGylated FTn via an acid-labile linker to facilitate intracellular release of DOX after cell entry. Inhalation of DOX-loaded PEGylated FTn led to 60% survival, compared with 10% survival in the group that inhaled DOX in solution at the maximally tolerated dose, in a murine model of malignant airway lung cancer. This approach may provide benefits as an adjuvant therapy combined with systemic chemo-or immunotherapy or as a stand-alone therapy for patients with tumors confined to the airways. lung cancer | nanoparticle | biological barriers | PEG | human ferritin

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Section: Resultsmentioning

confidence: 57%

Protein nanocages that penetrate airway mucus and tumor tissue

Chisholm

Zhuang

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

100

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“…Indeed, these images confirmed the properties of doxorubicin as described in the literature in its function as a DNA intercalator. 17 Furthermore, the uptake profile of CDN dox and free doxorubicin in a Flow Activated Cell Sorting (FACS) assay seemed to indicate a similar uptake profile at both 1 and 6-h incubation time points, suggesting that CDN dox are taken up by the cells at a similar rate as free doxorubicin ( Figure 4B). This is in contrast with the release ° study, where free doxorubicin crosses the semi-permeable membrane at almost twice the rate as CDN dox loaded from Method A.…”

Section: Cellular Uptake Studiesmentioning

confidence: 90%

Doxorubicin-loaded cell-derived nanovesicles: an alternative targeted approach for anti-tumor therapy

Goh

Lee

Zou

et al. 2017

IJN

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Cell-derived nanovesicles (CDNs) are an emerging class of biological drug delivery systems (DDS) that retain the characteristics of the cells they were derived from, without the need for further surface functionalization. CDNs are also biocompatible, being derived from natural sources and also take advantage of the enhanced permeability and retention effect due to their nanodimensions. Furthermore, CDNs derived from monocytes were shown to have an in vivo targeting effect, accumulating at the tumor site in a previous study conducted in a mouse tumor model. Here, we report a systematic approach pertaining to various loading methods of the chemotherapeutic drug doxorubicin into our CDNs and examine the differential cellular uptake of drug-loaded CDNs in cancerous (HeLa) and healthy (HEK293) cell lines. Lastly, we proved that the addition of doxorubicin-loaded CDNs to the HeLa and HEK293 co-cultures showed a clear discrimination toward cancer cells at the cellular level. Our results further reinforce the intriguing potential of CDNs as an alternative targeted strategy for anticancer therapy.

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“…50,51 The significant decrease in DOX IC 50 values in our cell lines after treatment with DOX-loaded PBCA NPs could be explained by the greater degree of drug incorporation into the cell when the NP biodegrades in the endosome and releases the DOX before finally reaching the nucleus. 51,52 On the other hand, when DOX-loaded PBCA NPs were administered to tumor-bearing mice, a significantly greater inhibition of tumor growth (40%) was obtained in comparison with free DOX. This observation represents a substantial improvement in drug activity against breast cancer tumors.…”

Section: 31mentioning

confidence: 99%

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

Cabeza¹,

Ortíz²,

Arias³

et al. 2015

IJN

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The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC 50 ) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers.

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Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells

Cited by 104 publications

References 47 publications

Protein nanocages that penetrate airway mucus and tumor tissue

Protein nanocages that penetrate airway mucus and tumor tissue

Doxorubicin-loaded cell-derived nanovesicles: an alternative targeted approach for anti-tumor therapy

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

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