Degradable multifunctional gold-liposomes as an all-in-one theranostic platform for image-guided radiotherapy

https://doi.org/10.1016/j.ijpharm.2022.122413Get rights and content

Abstract

To improve tumor destruction and minimize adverse effects to healthy tissues, image-guided radiation therapy (IGRT) has been developed to allow for the accurate delivery of radiation energy to tumor sites facilitated by real-time imaging. Nevertheless, the current IGRT platform still suffers from the limitation of poor tissue contrast, resulting in the incidental irradiation of healthy tissue. Gold nanoparticles (GNPs) have been identified as promising candidates to simultaneously improve both radiotherapy and imaging, thereby improving both the accuracy and safety of IGRT. However, despite much preclinical study, little clinical progress has been made due to uncertainty over GNP toxicity. Herein, we demonstrate the great potential of using GNP-coated liposomes, i.e., Lipogold, which combine the advantages of both large and small nanoparticles into one multifunctional formulation, as an ideal platform for IGRT. When irradiated with low doses (<2 Gy) of therapeutic X-rays, Lipogold induced a significant radiosensitization effect for PC-3 prostate cancer cells, which are moderately radiation-resistant. When imaged with computed tomography (CT), Lipogold was also found to possess consistent X-ray contrast of ∼ 18–23 HU/mg across tube X-ray voltages (70–140 kVp), which could be boosted via the encapsulation of a small-molecule contrast agent containing iodine.

Section snippets

Background

Within the current landscape of oncology, radiation therapy (RT) is one of the major treatment options used today, with approximately 50 % of all patients receiving RT in some form (Baskar et al., 2012, McKelvey et al., 2018). Although RT is highly effective, it suffers from a lack of tissue selectivity, leading to numerous adverse effects in healthy tissues surrounding the tumor target. To improve tumor destruction and minimize adverse effects to healthy tissues, image-guided RT (IGRT) has

Materials

The prostate cancer cell lines PC-3 and DU-145 were purchased from American Type Culture Collection (ATCC) via Cedarlane, Burlington, ON, Canada. The Avanti Mini-Extruder, dipalmitoylphosphatidylcholine (DPPC; 25 mg/mL in chloroform), Sephadex G-50 powder, ascorbic acid, doxorubicin hydrochloride (DOX), thiazolyl blue tetrazolium bromide (MTT), iohexol, polyethylene glycol (PEG-20 k), Triton X-100, tetrachloroauric acid and methanol were purchased from Sigma Aldrich, Oakville, ON, Canada.

Synthesis and Characterization of Lipogold

To prepare Lipogold NPs, we adapted a robust method invented by Troutman et al. (Troutman et al., 2008) Using extruded pure DPPC liposomes as a template, the GNP shell was created by sequentially adding different ratios of gold chloride precursor and ascorbic acid. By varying the ratio of gold to ascorbic acid, a variety of blue-green colored nanoshells were produced, with more gold resulting in more intense and red-shifted plasmons (Fig. 2A and B). For consistency, we selected Lipogold

Discussion

Currently, one significant limitation of IGRT is a lack of viable contrast materials that can provide accurate delineation of the tumor’s margins, with large gold-based implants being the current method of choice; however, these large physical markers come with side effects such as inflammation, swelling, and bleeding that can complicate treatment prognosis. (Yin et al., 2022) Small molecule contrast agents containing iodine, while common in regular X-ray and CT imaging, have limited use in

Conclusions

In this work, our results indicate that Lipogold can be a powerful and highly customizable nanomedicine for IGRT in addition to phototherapy and chemotherapy. By combining gold and iodine for broad-spectrum CT imaging and maximizing Auger electron emission, Lipogold is an ideal platform for IGRT and its related combination strategies. While further work is needed to validate its efficacy in vivo, improve its tumor targeting, and identify the optimal formulations for encapsulating different

CRediT authorship contribution statement

Brian Youden: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing, Visualization. Feng Wang: Methodology. Xiaohan Zhang: Methodology, Investigation. Dennis Curry: Methodology, Investigation. Nicholas Majtenyi: Formal analysis, Investigation. Amani Shaaer: Formal analysis, Investigation. Kenneth Bingham: Methodology, Investigation. Quang Nguyen: Methodology, Investigation. Leslie Bragg: Resources, Writing – review &

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the Canada Research Chairs program, the NSERC Discovery Development Program, and Canada’s Telus Ride for Dad (RFD) and The Prostate Cancer Fight Foundation (PCFF).

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