To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes

Dou, Yannan N.; Hynynen, Kullervo; Allen, Christine

doi:10.1016/j.jconrel.2017.01.025

Cited by 153 publications

(97 citation statements)

References 109 publications

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“…1 Thermoresponsive drug delivery systems (TDDS) are sensitive to higher temperature (39°C-45°C) and release payload at target sites, ie, hyperthermic body tissues. 2 However, synthesis of the thermoresponsive hydrogels and liposomes generally involves synthesis of block copolymers via complex chemical reactions and use of potentially toxic reagents.…”

Section: Introductionmentioning

confidence: 99%

“…However, ThermoDox ® has short circulation life and should be administered immediately before radiofrequency ablation. 1 Many embodiments of thermoresponsive liposomes show low encapsulation efficiency (EE) 6 and unpredictable drug release, 3,7 and their blood circulation life is very short. 1,8 On the other hand, solid lipid nanoparticles (SLNs) have been reported to show long circulation life (24 hours) and passively target cancers by enhanced permeability and retention (EPR) effect.…”

mentioning

confidence: 99%

“…1 Many embodiments of thermoresponsive liposomes show low encapsulation efficiency (EE) 6 and unpredictable drug release, 3,7 and their blood circulation life is very short. 1,8 On the other hand, solid lipid nanoparticles (SLNs) have been reported to show long circulation life (24 hours) and passively target cancers by enhanced permeability and retention (EPR) effect. 9,10 In addition to this, SLN composition and their methods of preparation are considered safe as compared to other novel DDS such as liposomes.…”

mentioning

confidence: 99%

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Solid lipid nanoparticles for thermoresponsive targeting: evidence from spectrophotometry, electrochemical, and cytotoxicity studies

Rehman¹,

Ihsan²,

Madni³

et al. 2017

IJN

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Thermoresponsive drug delivery systems are designed for the controlled and targeted release of therapeutic payload. These systems exploit hyperthermic temperatures (>39°C), which may be applied by some external means or due to an encountered symptom in inflammatory diseases such as cancer and arthritis. The objective of this paper was to provide some solid evidence in support of the hypothesis that solid lipid nanoparticles (SLNs) can be used for thermoresponsive targeting by undergoing solid–liquid phase transition at their melting point (MP). Thermoresponsive lipid mixtures were prepared by mixing solid and liquid natural fatty acids, and their MP was measured by differential scanning calorimetry (DSC). SLNs (MP 39°C) containing 5-fluorouracil (5-FU) were synthesized by hot melt encapsulation method, and were found to have spherical shape (transmission electron microscopy studies), desirable size (<200 nm), and enhanced physicochemical stability (Fourier transform infrared spectroscopy analysis). We observed a sustained release pattern (22%–34%) at 37°C (5 hours). On the other hand, >90% drug was released at 39°C after 5 hours, suggesting that the SLNs show thermoresponsive drug release, thus confirming our hypothesis. Drug release from SLNs at 39°C was similar to oleic acid and linoleic acid nanoemulsions used in this study, which further confirmed that thermoresponsive drug release is due to solid–liquid phase transition. Next, a differential pulse voltammetry-based electrochemical chemical detection method was developed for quick and real-time analysis of 5-FU release, which also confirmed thermoresponsive drug release behavior of SLNs. Blank SLNs were found to be biocompatible with human gingival fibroblast cells, although 5-FU-loaded SLNs showed some cytotoxicity after 24 hours. 5-FU-loaded SLNs showed thermoresponsive cytotoxicity to breast cancer cells (MDA-MB-231) as cytotoxicity was higher at 39°C (cell viability 72%–78%) compared to 37°C (cell viability >90%) within 1 hour. In conclusion, this study presents SLNs as a safe, simple, and effective platform for thermoresponsive targeting.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Solid lipid nanoparticles for thermoresponsive targeting: evidence from spectrophotometry, electrochemical, and cytotoxicity studies

Rehman¹,

Ihsan²,

Madni³

et al. 2017

IJN

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“…[66] One stimuli-responsive nanomedicine to reach the advanced clinical stage is the thermosensitive lyso-liposomal formualtion (Thermodox) encapsulating doxorubicin and releasing the drug upon heating to 40−45 °C due to the structural changes (pore formation) in the liposomes. [121] Despite of this advanced stimuli-responsive nanomedicine, the majority of the nanomedicines are regarded to slowly release the drugs in the systemic circulation, as a result of the long circulating time and slow extravasation, which most likely lead to a lower drug concentration when they reach the tumor and associated tumor microenvironment (TME). In addition, given that recent analysis showed only about 0.7% of the injected dose of nanomedicines actually accumulate in the tumors, suggesting that less amount of nanomedicines reaching the tumor site may further reduce the drug dose at the tumor.…”

Section: Controlled Drug Releasementioning

confidence: 99%

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Balasubramanian

Liu

Hirvonen

et al. 2017

Adv Healthcare Materials

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Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.

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“…These technologies may use nano-or micro-scale drug carriers that release a drug after ultrasound raises the in situ temperature, 8,9 activates a 'sonosensitizer', 10 or applies a sufficient peak intensity or pressure 5,11 . While high-intensity continuous wave ultrasound (for temperature-gated systems) may be difficult to achieve stably in certain regions of the body, 12 raising the peak pressure or intensity necessitates only short bursts of ultrasound that are more straightforward to achieve in situ.…”

mentioning

confidence: 99%

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

Zhong

Yoon

Aryal

et al. 2018

Preprint

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The holy grail of drug delivery nanotechnology is the ability to target the right drug to the right part of the body at the right time. Here, we demonstrate that polymeric perfluoropentane nanoemulsions are a generalized platform for targeted drug delivery with high potential for clinical translation. We delineate a production protocol optimized for nanoparticle size, monodispersity, drug loading, and stability, and hew to clinical production standards. We confirm that varied drugs may be effectively uncaged with ultrasound using this nanoparticle system, with drug loading increasing with hydrophobicity. Finally, we exhibit the in vivo efficacy of this system in two organ systems: we enable targeted modulation of brain activity with anesthetic uncaging and we locally control cardiovascular function with vasodilator uncaging. This work establishes the power of polymeric perfluoropentane nanoemulsions as a clinically-translatable platform for noninvasive ultrasonic drug uncaging for myriad targets in the brain and body.

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To heat or not to heat: Challenges with clinical translation of thermosensitive liposomes

Cited by 153 publications

References 109 publications

Solid lipid nanoparticles for thermoresponsive targeting: evidence from spectrophotometry, electrochemical, and cytotoxicity studies

Solid lipid nanoparticles for thermoresponsive targeting: evidence from spectrophotometry, electrochemical, and cytotoxicity studies

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

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