The PEGylated liposomal doxorubicin improves the delivery and therapeutic efficiency of ¹⁸⁸Re-Liposome by modulating phagocytosis in C26 murine colon carcinoma tumor model

Abstract

Liposome in delivering radionuclide for cancer therapy has been expansively studied; however, liposome itself can be deliberately entrapped and destroyed by the reticuloendothelial system, causing an insufficiency of the drug delivery, which in turn would restrict the effectiveness of the drug. In this study, mice with subcutaneous implantation of C26 murine colon cancer received an experimental treatment regimen in which mice took delivery of PEGylated liposomal doxorubicin (LipoDox) first, after a three-day interval, of Rhenium-188 encapsulated into PEGylated liposome (¹⁸⁸Re-Liposome) subsequently and by which suppressed the functioning of reticuloendothelial system for the short term. The data showed that based upon the biodistribution assay and the evaluation of the therapeutic efficacy, ¹⁸⁸Re-Liposome was more sufficiently delivered to tumor sites in mice with this treatment regimen than mice without the regimen, and that cancer mortalities in mice with the treatment regimen were much lower than the mortalities in mice without the regimen. Taken together, a new strategy proposed in this study significantly improved both the ¹⁸⁸Re-Liposome delivery and the effectiveness of ¹⁸⁸Re-Liposome, suggesting that the strategy can be an ideal treatment for cancer.

Introduction

Over the past two decades, nanoscale particles in the drug delivery have been widely studied, for they can precisely deliver the medicine and advantageously minimize side effects [1], [2]. Among them, it is liposome that can be proved one of the most successful approaches for treatment of disease, including cancer therapy [3], [4]. Nanoliposome, with a certain particle size (≤ 200 nm), can passively accumulate in tumor sites through leaky vessels [5], [6]. This phenomenon is called the enhanced permeability and retention (EPR) effects, which is now to be practical for most types of rapidly growing solid tumors; also, liposome-type drugs showed of having increased retention time in comparison with free-type ones [7], [8]. However, it had been known that liposome was cleared and destroyed naturally by immune responses, particularly the hepatic Kupffer cells in the reticuloendothelial system (RES) [9], [10].

Polyethylene glycol has been applied either to improve the stability or to avoid the immunogenicity of liposome [11], [12]; however, the surface modification of liposome with this polymer cannot totally protect it from destruction by immune reactions [13], [14], [15]. As a result, several strategies were performed to prevent nanoparticles from being captured by RES through phagocytosis, such non-spherical particles as hexagonal nano-prisms [16] or filomicelles [17]. Unlike special geometry of nanoparticles, another strategy was showed of having an effect that depletes the number of hepatic Kupffer cells, which can increase the circulation time of liposome-type drugs in blood stream [18]; hence, this provides an alternative approach to treating cancer: pretreatment of PEGylated liposomal doxorubicin, a clinically approved nano-drug, in experimental mice for prolonging the half-time of another therapeutic nanoparticle.

In cancer treatment, for example, internal radiation therapy is radiation delivered from radioactive materials, such as beta-emitting radionuclides—¹³¹I and ⁹⁰Y [19], [20]. Although a few radionuclides have been successfully used in clinics, some of which have potential benefits just as well as Rhenium-188 (¹⁸⁸Re) does [21]. ¹⁸⁸Re is the radionuclide with 2.12-MeV beta particles and 155-keV gamma proton, making itself suitable for nuclear medical imaging and radionuclide therapy [22]. In addition, the theranostic strategy, a method of combining both diagnostics and therapeutics, has emerged in the field of nanomedicine for its advantages of identifying illness, of delivering drugs, and of monitoring therapeutic effects [4], [23]. Taking these together, it forms the basis for developing this bi-functional radionuclide encapsulated nanoparticles [24], [25], [26].

In this study, Rhenium-188 encapsulated liposomes (¹⁸⁸Re-Liposomes) were prepared, and its therapeutic effect was evaluated in a subcutaneous implantation model of murine colon cancer [27], [28], and not only that, but PEGylated liposomal doxorubicin effective in decreasing the function of hepatic Kupffer cells and in increasing the passive targeting efficiency of ¹⁸⁸Re-Liposome was examined in same model.