Liposomal IR-780 as a Highly Stable Nanotheranostic Agent for Improved Photothermal/Photodynamic Therapy of Brain Tumors by Convection-Enhanced Delivery.

Yu-Jen Lu,Chi-Cheng Chuang,Anilkumar T S,Jyh-Ping Chen

doi:10.3390/cancers13153690

Abstract

Simple SummaryTo improve the use of hydrophobic photosensitizer IR-780 in photothermal/photodynamic therapy (PTT/PDT), we entrap IR-780 within the lipid bilayer of liposomes (ILs). Compared to free IR-780, ILs showed well-preserved photothermal response by maintaining the photostability of IR-780 from repeated near infrared (NIR) laser exposure both in vitro and in vivo. Combined with fast endocytosis by human glioblastoma cells, ILs demonstrated enhanced cytotoxicity and induced higher cell apoptosis rate toward human glioblastoma cells over free IR-780, due to PTT with overexpression of heat shock protein and PDT with generation of intracellular reactive oxygen species. To overcome the blood–brain barrier, we used convection enhanced delivery (CED) for specific delivery of ILs to brain tumors in intracranial glioma xenograft. Upon three successive NIR laser irradiations, the liposomal IR-780 could significantly improve the anti-cancer efficacy in glioma treatment, leading to diminished intracranial tumor size and prolonged animal survival time.As a hydrophobic photosensitizer, IR-780 suffers from poor water solubility and low photostability under near infrared (NIR) light, which severely limits its use during successive NIR laser-assisted photothermal/photodynamic therapy (PTT/PDT). To solve this problem, we fabricate cationic IR-780-loaded liposomes (ILs) by entrapping IR-780 within the lipid bilayer of liposomes. We demonstrate enhanced photostability of IR-780 in ILs with well-preserved photothermal response after three repeated NIR laser exposures, in contrast to the rapid decomposition of free IR-780. The cationic nature of ILs promotes fast endocytosis of liposomal IR-780 by U87MG human glioblastoma cells within 30 min. For PTT/PDT in vitro, ILs treatment plus NIR laser irradiation leads to overexpression of heat shock protein 70 and generation of intracellular reactive oxygen species by U87MG cells, resulting in enhanced cytotoxicity and higher cell apoptosis rate. Using intracranial glioma xenograft in nude mice and administration of ILs by convection enhanced delivery (CED) to overcome blood-brain barrier, liposomal IR-780 could be specifically delivered to the brain tumor, as demonstrated from fluorescence imaging. By providing a highly stable liposomal IR-780, ILs significantly improved anti-cancer efficacy in glioma treatment, as revealed from various diagnostic imaging tools and histological examination. Overall, CED of ILs plus successive laser-assisted PTT/PDT may be an alternative approach for treating brain tumor, which can retard glioma growth and prolong animal survival times from orthotopic brain tumor models.

Highlights

Photothermal therapy (PTT) is one of the least invasive therapeutic modalities for cancer treatment with minimum toxicity
From the distribution curve of hydrodynamic diameter measured by DLS (Figure 1B) and zeta potential (Figure 1C), the average size and zeta potential was 136.6 ± 5.5 nm and 33.3 ± 5.1 mV, with a polydispersity index (PDI) of
By entrapping IR-780 within the lipid bilayer of cationic liposomes to maintain its photostability during successive near infrared (NIR) laser irradiation, we successfully prepared IR-780-loaded liposomes (ILs) in this study and demonstrated its improved photothermal/photodynamic therapy (PTT/photodynamic therapy (PDT)) of intracranial glioma after convention-enhanced delivery (CED)

Summary

Introduction

Photothermal therapy (PTT) is one of the least invasive therapeutic modalities for cancer treatment with minimum toxicity It mainly uses light, usually in the near-infrared (NIR) range for maximum tissue penetration, to directly kill cancer cells while converting light energy into heat. One of major concerns of PTT is the drainage of generated heat into the tumor vicinity, which could lead to unintended damage to neighboring non-tumor cells [4]. This difficulty could be overcome by using a PA for locally induced heat generation upon NIR light irradiation, where selective cancer cell killing occurs only after the intracellular uptake of the PA [5]. Other than ICG, many inorganic nanomaterials such as magnetic nanoparticles, Au nanorods and carbon-based nanomaterials are good PAs [6]

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