Acid-sensitive Lipidated Doxorubicin Prodrug Entrapped in Nanoemulsion Impairs Lung Tumor Metastasis in a Breast Cancer Model

Camara, Ana Lygia dos Santos; Nagel, Gregor; Tschiche, Harald R.; Cardador, Camila Magalhães; Muehlmann, Luís Alexandre; Oliveira, Dutra de; Alvim, Paula Queiroz; Azevedo, Ricardo Bentes; Calderón, Marcelo; Longo, João Paulo Figueiró

doi:10.2217/nnm-2017-0091

Cited by 32 publications

(15 citation statements)

References 35 publications

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“…Based on the available literature, we hypothesise that both the free and encapsulated Dox-PSA are taken up by PC cells via caveolae-mediated endocytosis (CME), in contrast to free Dox which is known to freely diffuse across the plasma membrane and readily localise in the nucleus 60 . Indeed, this endocytic pathway had previously been reported for pH-sensitive liposomes 23,61 .…”

Section: Discussionmentioning

confidence: 99%

Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug: A Key Feature Toward Prodrug-Nanomedicine Design

et al. 2019

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was in phase I clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). It consists of doxorubicin (Dox) conjugated to a prostate specific antigen (PSA)-cleavable peptide that can be selectively activated by secreted PSA at the tumor site. However, despite the initial promising results, further clinical testing with Dox-PSA was halted due to toxicity concerns emerging from non-PSA-specific cleavage, following systemic administration.In the present study, we have reported, for the first time, the intracellular activation of Dox-PSA, where Dox nuclear uptake was specific to C4-2B (PSA-expressing) cells, which agreed with the cytotoxicity studies. This finding was confirmed by encapsulating Dox-PSA prodrug into pH-sensitive liposomes to enable prodrug intracellular release, followed by its enzymatic activation. Interestingly, our results demonstrated that Dox-PSA loaded into pH-responsive nanoparticles exhibited cytotoxicity comparable to free prodrug in C4-2B monolayers, with superior activity in tumor spheroids, due to deeper penetration within tumor spheroids. Our approach could open the doors for novel Dox-PSA nanomedicines with higher safety and efficacy to treat advanced and metastatic prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug: A Key Feature Toward Prodrug-Nanomedicine Design

et al. 2019

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“…oil and water) can be achieved through emulsification methods, which are broadly classified as either high- or low-energy processes 27–30 . Nanoscale emulsions with sizes on the order of 100 nm (so-called nanoemulsions) provide an efficient and facile approach to encapsulating both polar and non-polar functional biomolecules for co-delivery of dissimilar therapeutics 31–33 . Multiple strategies have been employed to obtain thermogelling emulsion-based organohydrogels which are mostly based on entrapping the dispersed phase via thermally gelling the continuous phase 34–37 .…”

Section: Introductionmentioning

confidence: 99%

Thermoresponsive nanoemulsion-based gel synthesized through a low-energy process

et al. 2019

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Thermoresponsive nanoemulsions find utility in applications ranging from food to pharmaceuticals to consumer products. Prior systems have found limited translation to applications due to cytotoxicity of the compositions and/or difficulties in scaling-up the process. Here, we report a route to thermally gel an oil-in-water nanoemulsion using a small amount of FDA-approved amphiphilic triblock Pluronic copolymers which act as gelling agents. At ambient temperature the suspension displays liquid-like behavior, and quickly becomes an elastic gel at elevated temperatures. We propose a gelation mechanism triggered by synergistic action of thermally-induced adsorption of Pluronic copolymers onto the droplet interface and an increased micelle concentration in the aqueous solution. We demonstrate that the system’s properties can be tuned via many factors and report their rheological properties. The nanoemulsions are prepared using a low-energy process which offers an efficient route to scale-up. The nanoemulsion formulations are well-suited for use in cosmetics and pharmaceutical applications.

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“…For liver, spleen and lungs, no statistically significant difference was observed between the experimental groups, but in all these organs NCS-DOX had a higher DOX signal compared to the free DOX treatment. As they are highly vascularized organs, this event is commonly reported in the literature [13]. For heart analysis, no significant DOX signal was detected.…”

Section: Discussionmentioning

confidence: 62%

“…For tumour induction, a previously described protocol was used [10,13]. Briefly, animals were first anesthetized with 100 mL solution of ketamine hydrochloride and xylazine (0.8 and 0.1 mg/kg, respectively), injected intraperitoneally.…”

Section: Animals and Tumour Inductionmentioning

confidence: 99%

Selol nanocapsules with a poly(methyl vinyl ether-co-maleic anhydride) shell conjugated to doxorubicin for combinatorial chemotherapy against murine breast adenocarcinoma in vivo

Ganassin

Horst

Camargo

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Nanocapsules containing selol and doxorubicin (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed in a previous work. In this study, these nanocapsules showed a similar antitumour effect in comparison to the free doxorubicin (DOX) treatment, but showed no evident DOX-related cardiotoxicity, as evidenced by serum creatine kinase-MB (CK-MB) activity. The histopathological analysis showed that the free DOX treatment induced more intense morphological damage to myocardial tissues in comparison to NCS-DOX treatment. Animals treated with free DOX presented important muscle fibre degradation and animals treated with NCS-DOX, heart tissue did not present signals of muscle fibre degeneration. These results indicate that the cardiotoxicity related to DOX is reduced when this drug is carried by the NCS-DOX. Noteworthy, biodistribution analyses showed that NCS-DOX accumulated more intensely in tumours than the free DOX. Thus, this study reinforces the importance of the development of nanocapsules as drug carriers for the treatment of cancer.

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Acid-sensitive Lipidated Doxorubicin Prodrug Entrapped in Nanoemulsion Impairs Lung Tumor Metastasis in a Breast Cancer Model

Abstract: Taken together, these results indicate that NE-C16-Dox is promising for breast cancer treatment, thus creating possibilities to translate these nanotechnology concepts to clinical applications.

Cited by 32 publications

References 35 publications

Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug: A Key Feature Toward Prodrug-Nanomedicine Design

Intracellular Activation of a Prostate Specific Antigen-Cleavable Doxorubicin Prodrug: A Key Feature Toward Prodrug-Nanomedicine Design

Thermoresponsive nanoemulsion-based gel synthesized through a low-energy process

Selol nanocapsules with a poly(methyl vinyl ether-co-maleic anhydride) shell conjugated to doxorubicin for combinatorial chemotherapy against murine breast adenocarcinoma in vivo

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