Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

Abstract

Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle ͑liposome͒-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods:99m Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, 186Re / 188Re liposomes. Effective uniform dose ͑EUD͒ and tumor control probability ͑TCP͒ were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq ͑318.2 Gy/mCi͒ and 5.7 Gy/MBq ͑209.1 Gy/mCi͒ could be delivered with this protocol of radiation delivery for 186 Re / 188Re liposomes, respectively, and 37-92 MBq ͑1-2.5 mCi͒/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy beta emissions, dose escalation through increased specific activity, and increasing the number of direct tumor infusion sites improve tumor control. For larger tumors, the use of multiple infusion locations was modeled to be much more efficient, in terms of activity usage, at improving EUD and TCP to achieve a tumoricidal effect. Conclusions: Direct intratumoral infusion of beta-emitting radionuclide encapsulated liposomes shows promise for cancer therapy by achieving large focally delivered tumor doses. However, the results of this work also indicate that average tumor dose may underestimate tumoricidal effect due to substantial heterogeneity in intratumoral liposomal radionuclide distributions. The resulting intratumoral distribution of liposomes following infusion should be taken into account in treatment planning and evaluation in a clinical setting for an optimal cancer therapy.

Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated186Re radionuclides

“…It is also clear that considerable levels of average tumour doses were delivered for each rat for low levels of infused activity; however, calculated EUD values are much lower due to regions of the tumour receiving inadequate dose. This distinction has previously been seen (Prideaux et al 2007, Hrycushko et al 2011b). Table 2 shows therapy response as calculated by relative volume change; that is, ratio of final day 43 tumour volume to initial day 0 tumour volume.…”

“…The animal study in this work was performed to evaluate the improved therapy effect when using infused 186 Re-liposomes following neoadjuvant bevacizumab therapy as well as comparing the treatment effect when using multiple versus single intratumoural infusion locations as predicted by a previous 99m Tc-liposome imaging study (Hrycushko et al 2011b). This paper reports on the tumour dose-response relationship by correlating intratumoural dosimetric and radiobiological index calculations from in vivo small animal micro-SPECT/CT images with tumour volume changes and is not meant to compare and contrast treatment groups.…”

“…Simple absorbed dose escalation may be inefficient in achieving adequate tumour absorbed dose coverage for tumour control. (O'Donoghue 1999, Prideaux et al 2007, Kalogianni et al 2007, Amro et al 2010, Hrycushko et al 2011b). …”

Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles

“…β-Emitting radionuclides which also emit gamma photons for diagnostic imaging purposes are shown in Table 1. This theranostic capability of specific β-emitting therapeutic radionuclides has proven very useful in the development of rhenium-nanoparticle intratumoral therapies, permitting visualization and quantification of the distribution of these nanoparticles within the tumor and in the various organs of the body on a percent injected dose basis using non-invasive imaging [64,66,91,142,146,155]. …”

Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor

“…These include the complicated placement procedures required for seed insertion, post-treatment excision of the seed implants, and occasional brachytherapy seed migration [3]. To improve upon these issues, polymeric nanoparticles carrying therapeutic radionuclides have recently been developed and demonstrated some success for use in brachytherapy [4–7]. Before these materials can be translated to clinical application, though, several delivery concerns must overcome.…”