Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency

Dawidczyk, Charlene M.; Russell, Luisa M.; Hultz, Margot; Searson, Peter C.

doi:10.1016/j.nano.2017.02.008

Cited by 32 publications

(26 citation statements)

References 28 publications

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“…Hence, it is a common model drug for constructing drug delivery vehicles. Several studies have shown Dox loading to different carriers such as liposomes, polymeric nanoparticles, nanomicelles, and others . However, to the best of our knowledge, there is a lack of reports on the use of RuNPs.…”

Section: Discussionmentioning

confidence: 99%

pH-Responsive Hybrid Organic-Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubicin

Buchtelová

Strmiska

Dostálová

et al. 2017

Part. Part. Syst. Charact.

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The current study aims at preparing biocompatible hybrid organic–inorganic ruthenium core–shell nanostructures (RuNPs) coated with polyvinylpyrrolidone (PVP) and polyoxyethylene stearate (POES). Thereafter, the core/shell RuNPs are loaded with doxorubicin (to form RuPDox) with a loading efficiency > 60%. RuPDox possesses exceptional stability and pH‐responsive release kinetics with approx. 50% release of doxorubicin at up to 1 h exposure to an acidic endosomal environment. The cytotoxic effects of RuPDox are tested in vitro against breast cancer (MDA‐MB‐231), ovarian cancer (A2780), and neuroblastoma (UKF‐NB‐4) cells. Notably, although RuNPs have slight cytotoxicity only, RuPDox causes a synergistic enhancement of cytotoxicity when compared to free doxorubicin. Significant increase in free radicals formation, enhanced activity of executioner caspases 3/7, and higher expression of p53 and metallothionein is further identified due to the RuPDox treatment. Single‐cell gel electrophoresis reveals no additional contribution of RuNPs to genotoxicity of doxorubicin. Moreover, RuPDox promotes significantly increased stability of doxorubicin in human plasma and pronounced hemocompatibility assayed on human red blood cells. The results imply a high potential of biocompatible hybrid RuNPs with PVP‐POES shell as versatile nanoplatforms to enhance the efficiency of cancer treatment.

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Section: Discussionmentioning

confidence: 99%

pH-Responsive Hybrid Organic-Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubicin

Buchtelová

Strmiska

Dostálová

et al. 2017

Part. Part. Syst. Charact.

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“… 23 By contrast, the LTLD formulation that we used in this trial is understood to act by rapid diffusion of doxorubicin into the tumour interstitium under conditions of mild hyperthermia, with only a small proportion of doxorubicin entering the tumour by enhanced permeability and retention. These intended delivery mechanisms are reflected in the circulation profiles of the two formulations, with NTLD having a half-life of more than 10 h while LTLD has a shorter half-life of about 1 h. 9 , 10 , 24 , 25 …”

Section: Discussionmentioning

confidence: 99%

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Lyon

Gray

Mannaris

et al. 2018

The Lancet Oncology

178

122

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SummaryBackgroundPrevious preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.MethodsWe did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.FindingsBetween March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.InterpretationThe combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.FundingOxford Biomedical Research Centre, National Institute for Health Research.

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“…Regardless, some general trends could be observed for factors leading to poorly fitted data, such as when the plasma particle concentrations reported were consistently lower than tumor values [55–57]: a puzzling scenario considering that systemically-administered particles ought to have the highest concentration in the blood pool before being distributed to various organs. The tumor concentration values may also have high variability with no observable trend with respect to time [58,59], or achieved high levels within an hour and appear to plateau despite particle clearance from the bloodstream [60–62], which may indicate lasting retention in the tumors (see examples in Supplementary Information). Some of these cases may have arisen from differences in methods employed for measuring particle concentration in the blood and tumor (e.g.…”

Section: Resultsmentioning

confidence: 99%

Diffusive Flux Analysis of Tumor Vascular Permeability for 3-Helix-Micelles in Comparison to Other Nanoparticles

Lim

Dharmaraj²,

Gong³

et al. 2019

Preprint

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Understanding the complex interplay of factors affecting nanoparticle accumulation in solid tumors is a challenge that must be surmounted to develop effective cancer nanomedicine. The tumor microenvironment is unique in comparison to healthy tissue, possessing elevated interstitial pressure that limits convective transport, hence leaving diffusive processes to predominate especially in the tumor necrotic core. Certain tumor types such as glioblastoma multiforme and pancreatic tumor are known to be poorly permeable, making them less accessible for nanoparticle drug delivery. Evidence indicates that small and long-circulating nanoparticles are ideal for taking advantage of the enhanced permeability and retention effect, even in such intractable tumor models. Three-helix-micelle (3HM) self-assembled nanoparticles possess these characteristics, and previous studies have shown that 3HM can achieve more favorable tumor accumulation and penetration than liposomes in several tumor models. The reason for its superior performance had yet to be determined, and thus we sought to examine its passive transport into tumors. In this paper we present a simple mathematical model based on diffusive flux to describe particle accumulation in tumors with respect to particle plasma pharmacokinetics. Fitting the diffusive flux equation to in vivo particle tumor concentration yields the particle effective permeability value, which for 3HM is 2.31 ± 0.18 x 10-8 cm/s in U87MG glioblastoma and 4.25 ± 0.91 x 10-8 cm/s in HT29 colon cancer murine models. Applying this diffusive flux model to other nanoparticles reported in literature enables the effect of plasma half-life to be decoupled from particle permeability in influencing tumor accumulation, reinforced trends reported in the field regarding the impact of particle size, and provided a semi-quantitative means of comparing various tumor models. This work is also the first demonstration, to the best our knowledge, of extracting particle permeability values from bulk biodistribution data obtained via positron emission tomography, as opposed to laborious tumor optical window intravital microscopy experiments. As such the analysis provided here presents a simple and accessible tool to further enhance nanomedicine development.

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Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency

Cited by 32 publications

References 28 publications

pH-Responsive Hybrid Organic-Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubicin

pH-Responsive Hybrid Organic-Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubicin

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Diffusive Flux Analysis of Tumor Vascular Permeability for 3-Helix-Micelles in Comparison to Other Nanoparticles

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