Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes

Motamarry, Anjan; Negussie, Ayele H.; Rossmann, Christian; Small, James; Wolfe, Amber; Wood, Bradford J.; Haemmerich, Dieter

doi:10.1080/02656736.2019.1642521

Cited by 25 publications

(32 citation statements)

References 46 publications

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“…For example, ThermoDox® preclinical development information strongly suggests that the heating of the tumour needs to precede injection of the TSL 8 . Other studies have demonstrated effective treatment with FUS applied just before and then during infusion 46 , or immediately after injection 47 . In addition, the phase-III HEAT clinical trial computer modelling led to application of radiofrequency ablation 15 min post-infusion 48 and the TARDOX study indicated application of FUS shortly after infusion 20 .…”

Section: Resultsmentioning

confidence: 99%

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MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice

et al. 2021

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Rationale: Image-guided, triggerable, drug delivery systems allow for precisely placed and highly localised anti-cancer treatment. They contain labels for spatial mapping and tissue uptake tracking, providing key location and timing information for the application of an external stimulus to trigger drug release. High Intensity Focused Ultrasound (HIFU or FUS) is a non-invasive approach for treating small tissue volumes and is particularly effective at inducing drug release from thermosensitive nanocarriers. Here, we present a novel MR-imageable thermosensitive liposome (iTSL) for drug delivery to triple-negative breast cancers (TNBC). Methods: A macrocyclic gadolinium-based Magnetic Resonance Imaging (MRI) contrast agent was covalently linked to a lipid. This was incorporated at 30 mol% into the lipid bilayer of a thermosensitive liposome that was also encapsulating doxorubicin. The resulting iTSL-DOX formulation was assessed for physical and chemical properties, storage stability, leakage of gadolinium or doxorubicin, and thermal-or FUS-induced drug release. Its effect on MRI relaxation time was tested in phantoms. Mice with tumours were used for studies to assess both tumour distribution and contrast enhancement over time. A lipid-conjugated near-infrared fluorescence (NIRF) probe was also included in the liposome to facilitate the real time monitoring of iTSL distribution and drug release in tumours by NIRF bioimaging. TNBC (MDA-MB-231) tumour-bearing mice were then used to demonstrate the efficacy at retarding tumour growth and increasing survival. Results: iTSL-DOX provided rapid FUS-induced drug release that was dependent on the acoustic power applied. It was otherwise found to be stable, with minimum leakage of drug and gadolinium into buffers or under challenging conditions. In contrast to the usually suggested longer FUS treatment we identified that brief (~3 min) FUS significantly enhanced iTSL-DOX uptake to a targeted tumour and triggered near-total release of encapsulated doxorubicin, causing significant growth inhibition in the TNBC mouse model. A distinct reduction in the tumours' average T1 relaxation times was attributed to the iTSL accumulation. Conclusions: We demonstrate that tracking iTSL in tumours using MRI assists the application of FUS for precise drug release and therapy.

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Section: Resultsmentioning

confidence: 99%

“…NIRF imaging allows monitoring of the level of iTSL within the tumour compared to the rest of the body 46 . We selected it as a semi-quantitative but robust method that was expected to significantly facilitate clinical translation 51 .…”

Section: Resultsmentioning

confidence: 99%

MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice

et al. 2021

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“…Prior studies have employed HT durations as low as 2 min, with 60 min on the upper end [1,14,15]. Since longer HT enhances drug release and delivery for TSL [1,22,24], we employed two HT durations: 60 min to maximize delivery, and 15 min to evaluate the impact of a reduced HT duration.…”

Section: Discussionmentioning

confidence: 99%

Untargeted Large Volume Hyperthermia Reduces Tumor Drug Uptake From Thermosensitive Liposomes

Ramajayam

Wolfe

Motamarry

et al. 2021

IEEE Open J. Eng. Med. Biol.

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The impact of hyperthermia (HT) method on tumor drug uptake with thermosensitive liposomes (TSL) is not well understood. Methods: We created realistic three-dimensional (3-D) computer models that simulate TSL-encapsulated doxorubicin (TSL-DOX) delivery in mouse tumors with three HT methods (thermistor probe (T), laser (L) and water bath (WB), at 15 min and 60 min HT duration), with corroborating in vivo studies. Results: Average computer model-predicted tumor drug concentrations (µg/g) were 8.8(T, 15 min), 21.0(T, 60 min), 14.1(L, 15 min), 25.2(L, 60 min), 9.4(WB, 15 min), and 8.7(WB, 60 min). Tumor fluorescence was increased by 2.6x(T) and 1.6x(L) when HT duration was extended from 15 to 60 min (p<0.05), with no increase for WB HT. Pharmacokinetic analysis confirmed that water bath HT causes rapid depletion of encapsulated TSL-DOX in systemic circulation due to the large heated tissue volume. Conclusions: Untargeted large volume HT causes poor tumor drug uptake from TSL.INDEX TERMS Computer models, drug delivery, hyperthermia (HT), in vivo, thermosensitive liposomes IMPACT STATEMENT Untargeted large volume hyperthermia (HT) rapidly depletes systemically available thermosensitive liposomeencapsulated drug, resulting in low tumor drug uptake. Computer models established the cause for the observed differences in tumor drug uptake for varying HT methods.

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“…Combined with photodynamic activation, nanotechnology assists in developing advanced PS/drug formulations, targeting therapeutics, controlled delivery, and drug release for the treatment of various diseases (Fig. 11) [272][273][274][275]. These are unique attributes of PDT using nanotechnology and perhaps other externally activated therapies.…”

Section: Nanotechnology and Targeting In Pdtmentioning

confidence: 99%

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

Silva

Saad

Thomsen

et al. 2020

J. Porphyrins Phthalocyanines

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Photodynamic therapy is a photochemistry-based approach, approved for the treatment of several malignant and non-malignant pathologies. It relies on the use of a non-toxic, light activatable chemical, photosensitizer, which preferentially accumulates in tissues/cells and, upon irradiation with the appropriate wavelength of light, confers cytotoxicity by generation of reactive molecular species. The preferential accumulation however is not universal and, depending on the anatomical site, the ratio of tumor to normal tissue may be reversed in favor of normal tissue. Under such circumstances, control of the volume of light illumination provides a second handle of selectivity. Singlet oxygen is the putative favorite reactive molecular species although other entities such as nitric oxide have been credibly implicated. Typically, most photosensitizers in current clinical use have a finite quantum yield of fluorescence which is exploited for surgery guidance and can also be incorporated for monitoring and treatment design. In addition, the photodynamic process alters the cellular, stromal, and/or vascular microenvironment transiently in a process termed photodynamic priming, making it more receptive to subsequent additional therapies including chemo- and immunotherapy. Thus, photodynamic priming may be considered as an enabling technology for the more commonly used frontline treatments. Recently, there has been an increase in the exploitation of the theranostic potential of photodynamic therapy in different preclinical and clinical settings with the use of new photosensitizer formulations and combinatorial therapeutic options. The emergence of nanomedicine has further added to the repertoire of photodynamic therapy’s potential and the convergence and co-evolution of these two exciting tools is expected to push the barriers of smart therapies, where such optical approaches might have a special niche. This review provides a perspective on current status of photodynamic therapy in anti-cancer and anti-microbial therapies and it suggests how evolving technologies combined with photochemically-initiated molecular processes may be exploited to become co-conspirators in optimization of treatment outcomes. We also project, at least for the short term, the direction that this modality may be taking in the near future.

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Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes

Cited by 25 publications

References 46 publications

MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice

MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice

Untargeted Large Volume Hyperthermia Reduces Tumor Drug Uptake From Thermosensitive Liposomes

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

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