High Intratumoral Accumulation of Stealth Liposomal Doxorubicin in Sarcomas: Rationale for Combination with Radiotherapy

Mi, Koukourakis; Koukouraki, Sophia; Giatromanolaki, Alexandra; Kakolyris, S; Georgoulias,; Velidaki, Antigoni; Archimandritis, Spyridon C.; Nn, Karkavitsas

doi:10.1080/028418600430789

Cited by 103 publications

(25 citation statements)

References 18 publications

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“…As exemplified by Figure 7C-D, via such approaches, patients likely to respond to nanomedicine treatment can be pre-selected on the basis of non-invasive imaging (134-135). Convincing clinical proof-of-principle is available showing that tumors associated with a strong EPR effect, such as (Kaposi)_sarcomas and head-and-neck tumors, respond relatively well to (liposome-based) nanotherapeutics, whereas tumors that generally present with poor EPR, such as breast carcinomas, do not seem to benefit too much from such targeted interventions, at least not when it comes to increasing response rates and prolonging progression-free and overall survival times (8,134,136). It should be noted, however, that even in case of the latter, there are clear advantages of using nanomedicine formulations, but these are largely based on changing the nature and/or reducing the incidence and intensity of side effects, rather than on improving therapeutic outcome.…”

Section: Nanoparticle-based Theranosticsmentioning

confidence: 99%

“…B: Representative image of a glioblastoma patient treated with magnetic fluid hyperthermia using Nanotherm, depicting the primary tumor lesion (brown; MR assessment in the upper inset), the intratumorally administered magnetic fluid (blue; CT image in lower inset) and the thermometry catheter (green) (from (118) with permission). C: Gamma camera imaging of technetium-99m-labeled PEGylated liposomal doxorubicin (Doxil) in a patient suffering from Kaposi sarcoma of the palmer area of the hand, demonstrating the potential of using non-invasive imaging techniques to visualize and quantify the target site accumulation of nanomedicine formulations (from (136) with permission). D: Gamma camera imaging of drug targeting to the liver using an iodine-123-labeled sugar-modified polymer-drug conjugate (PK2), showing efficient liver localization (left panel), but inefficient tumor accumulation (upper right panel: distribution of PK2 within the liver; lower right panel: CT imaging of the central liver tumor).…”

Section: Essentialsmentioning

confidence: 99%

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Nanoparticles for Imaging: Top or Flop?

Kießling¹,

Mertens²,

Grimm³

et al. 2014

Radiology

193

146

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Nanoparticles are frequently suggested as diagnostic agents. However, except for iron oxide nanoparticles, diagnostic nanoparticles have been barely incorporated into clinical use so far. This is predominantly due to difficulties in achieving acceptable pharmacokinetic properties and reproducible particle uniformity as well as to concerns about toxicity, biodegradation, and elimination. Reasonable indications for the clinical utilization of nanoparticles should consider their biologic behavior. For example, many nanoparticles are taken up by macrophages and accumulate in macrophage-rich tissues. Thus, they can be used to provide contrast in liver, spleen, lymph nodes, and inflammatory lesions (eg, atherosclerotic plaques). Furthermore, cells can be efficiently labeled with nanoparticles, enabling the localization of implanted (stem) cells and tissue-engineered grafts as well as in vivo migration studies of cells. The potential of using nanoparticles for molecular imaging is compromised because their pharmacokinetic properties are difficult to control. Ideal targets for nanoparticles are localized on the endothelial luminal surface, whereas targeted nanoparticle delivery to extravascular structures is often limited and difficult to separate from an underlying enhanced permeability and retention (EPR) effect. The majority of clinically used nanoparticle-based drug delivery systems are based on the EPR effect, and, for their more personalized use, imaging markers can be incorporated to monitor biodistribution, target site accumulation, drug release, and treatment efficacy. In conclusion, although nanoparticles are not always the right choice for molecular imaging (because smaller or larger molecules might provide more specific information), there are other diagnostic and theranostic applications for which nanoparticles hold substantial clinical potential.

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Section: Nanoparticle-based Theranosticsmentioning

confidence: 99%

Section: Essentialsmentioning

confidence: 99%

Nanoparticles for Imaging: Top or Flop?

Kießling¹,

Mertens²,

Grimm³

et al. 2014

Radiology

193

146

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“…(▲) from [117] DOX concentration in tumor biopsies vs. plasma concentration, using DOX-containing PEGylated liposomes. (○) from [120], 99m Tc-DTPA-labelled liposomes tumor ROI vs. surrounding tissue (■) from [118], DOX concentration in bone metastases vs. plasma concentration, using Doxil®. All ratios are given for concentrations measured at the same time-point and individual patients are presented when possible; the doses of DOX used are labeled on the figure (closed symbols); open symbols represent the use of empty liposomes.…”

Section: Figurementioning

confidence: 99%

Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Bertrand

et al. 2014

Advanced Drug Delivery Reviews

2,422

1,814

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Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000’s. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.

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“…Moreover, as liposomes avoid accumulation in healthy tissue, radiation enhancement may primarily be located to tumors, reducing toxicities in neighboring healthy tissues [19,20]. Pegylated liposomal DXR (PL-DXR) has been shown to increase the effect of RT in preclinical studies [19,21].…”

Section: Introductionmentioning

confidence: 99%

“…Pegylated liposomal DXR (PL-DXR) has been shown to increase the effect of RT in preclinical studies [19,21]. Promising results have been demonstrated in clinical studies in sarcoma [20], as well as in locally advanced non-small cell lung cancer and head and neck cancer [22]. In prostate cancer, anthracyclines as free doxorubicin and epirubicin alone have shown to have a palliative effect on patients with incurable, metastatic, hormone-refractory prostate cancer [23].…”

Section: Introductionmentioning

confidence: 99%

Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts

2011

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BackgroundTumor vasculature frequently fails to supply sufficient levels of oxygen to tumor tissue resulting in radioresistant hypoxic tumors. To improve therapeutic outcome radiotherapy (RT) may be combined with cytotoxic agents.MethodsIn this study we have investigated the combination of RT with the cytotoxic agent doxorubicin (DXR) encapsulated in pegylated liposomes (PL-DXR). The PL-DXR formulation Caelyx® was administered to male mice bearing human, androgen-sensitive CWR22 prostate carcinoma xenografts in a dose of 3.5 mg DXR/kg, in combination with RT (2 Gy/day × 5 days) performed under normoxic and hypoxic conditions. Hypoxic RT was achieved by experimentally inducing tumor hypoxia by clamping the tumor-bearing leg five minutes prior to and during RT. Treatment response evaluation consisted of tumor volume measurements and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with subsequent pharmacokinetic analysis using the Brix model. Imaging was performed pre-treatment (baseline) and 8 days later. Further, hypoxic fractions were determined by pimonidazole immunohistochemistry of excised tumor tissue.ResultsAs expected, the therapeutic effect of RT was significantly less effective under hypoxic than normoxic conditions. However, concomitant administration of PL-DXR significantly improved the therapeutic outcome following RT in hypoxic tumors. Further, the pharmacokinetic DCE MRI parameters and hypoxic fractions suggest PL-DXR to induce growth-inhibitory effects without interfering with tumor vascular functions.ConclusionsWe found that DXR encapsulated in liposomes improved the therapeutic effect of RT under hypoxic conditions without affecting vascular functions. Thus, we propose that for cytotoxic agents affecting tumor vascular functions liposomes may be a promising drug delivery technology for use in chemoradiotherapy.

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High Intratumoral Accumulation of Stealth Liposomal Doxorubicin in Sarcomas: Rationale for Combination with Radiotherapy

Cited by 103 publications

References 18 publications

Nanoparticles for Imaging: Top or Flop?

Nanoparticles for Imaging: Top or Flop?

Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts

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