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Thermosensitive Exosome–Liposome Hybrid Nanoparticle?Mediated Chemoimmunotherapy for Improved Treatment of Metastatic Peritoneal Cancer

ABSTRACT: Abstract Metastatic peritoneal carcinoma (mPC) is a deadly disease without effective treatment. To improve treatment of this disease, a recently developed hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as the standard of care. However, the efficacy of this approach is limited by inefficient drug penetration and rapidly developed drug resistance. Herein, a nanotechnology approach is reported that is designed to improve drug delivery to mPC and to augment the efficacy of HIPEC through delivery of chemoimmunotherapy. First, the drug delivery efficiency of HIPEC is determined and it is found that chemotherapy agents cannot be efficiently delivered to large tumors nodules. To overcome the delivery hurdle, genetically engineered exosomes?thermosensitive liposomes hybrid NPs, or gETL NPs, are then synthesized, and it is demonstrated that the NPs after intravenous administration efficiently penetrates into mPC tumors and releases payloads at the hypothermia condition of HIPEC. Last, it is shown that, when granulocyte?macrophage colony?stimulating factor (GM?CSF) and docetaxel are co?delivered, gETL NPs effectively inhibit tumor development and the efficacy is enhanced when HIPEC is co?administered. The study provides a strategy to improve drug delivery to mPCs and offers a promising approach to improve treatment of the disease through combination of locoregional delivery of HIPEC and systemic delivery of chemoimmunotherapy via gETL NPs. In this study, a CD47 over expressed exosomes–liposomes hybrid nanoparticle (gETL NP) delivery system is developed for granulocyte?macrophage colony?stimulating factor (GM?CSF) and docetaxel co?delivery. Combined with standard hyperthermic intraperitoneal chemotherapy (HIPEC) therapy to metastatic peritoneal carcinoma (mPC), the gETL NP achieves HIPEC?mediated chemotherapy and CD47? and GM?CSF?mediated immunotherapy.

SUBMITTER: Lv Q

PROVIDER: S-EPMC7509655 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Project description:The promising potential of superparamagnetic iron oxide nanoparticles (SPIONs) in various nanomedical applications has been frequently reported. However, although many different synthesis methods, coatings, and functionalization techniques have been described, not many core-shell SPION drug delivery systems are available for clinicians at the moment. Here, bovine serum albumin was adsorbed onto lauric acid-stabilized SPIONs. The agglomeration behavior, zeta potential, and their dependence on the synthesis conditions were characterized with dynamic light scattering. The existence and composition of the core-shell-matrix structure was investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements. We showed that the iron oxide cores form agglomerates in the range of 80 nm. Moreover, despite their remarkably low tendency to aggregate even in a complex media like whole blood, the SPIONs still maintained their magnetic properties and were well attractable with a magnet. The magnetic properties were quantified by vibrating sample magnetometry and a superconducting quantum interference device. Using flow cytometry, we further investigated the effects of the different types of nanoparticle coating on morphology, viability, and DNA integrity of Jurkat cells. We showed that by addition of bovine serum albumin, the toxicity of nanoparticles is greatly reduced. We also investigated the effect of the particles on the growth of primary human endothelial cells to further demonstrate the biocompatibility of the particles. As proof of principle, we showed that the hybrid-coated particles are able to carry payloads of up to 800 ?g/mL of the cytostatic drug mitoxantrone while still staying colloidally stable. The drug-loaded system exhibited excellent therapeutic potential in vitro, exceeding that of free mitoxantrone. In conclusion, we have synthesized a biocompatible ferrofluid that shows great potential for clinical application. The synthesis is straightforward and reproducible and thus easily translatable into a good manufacturing practice environment.

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Thermosensitive Exosome–Liposome Hybrid Nanoparticle?Mediated Chemoimmunotherapy for Improved Treatment of Metastatic Peritoneal Cancer

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