Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles

Abstract

A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near-infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect.

Introduction

Indocyanine green (ICG), a tricarbocyanine dye with substantial absorption and fluorescence in the near-infrared wavelength region (NIR) and effective photothermal response, has been widely utilized as a probe for diagnostic and therapeutic applications [1], [2]. However, the applications of ICG in photothermal therapy and NIR imaging were restricted due to unstable optical properties, quick degradation and clearance in living body [3]. Various nanocarriers have been developed to encapsulate ICG and implement its enhanced penetration and retention (EPR) effect and fluorescence stability in vivo [4], [5].

Cancer nano-therapeutics is expected to solve limitation of conventional drug delivery system, such as improving drug accumulation in tumor tissue [6]. Recently, great progress has been achieved in improving drug pharmacokinetics, biodistribution and drug penetration in tumor tissue through versatile nanocarriers, considering multiple factors such as size, shape, surface charge and water solubility [7]. Therein, the size of nanomedicines shows a critical effect on passive targeting, and accumulation in tumor, which would influence their therapeutic efficacy [8], [9]. Additionally, the size control is also important in poorly permeable tumors like pancreatic carcinoma and colon carcinoma, which would induce limited drug distribution in tumors [6], [10], [11]. It has been proved that inorganic and polymer NPs with big size only accumulated near the vasculature while NPs with small size could rapidly diffuse throughout tumor matrix and provide a better penetration effect [12], [13], [14], [15], [16]. Therefore, it was necessary and urgent to validate the size control for improving drug biodistribution in vivo and EPR effect with enhanced therapeutic efficacy.

In this study, we developed ICG-loaded polymer-lipid NPs (INPs) with three different hydrodynamic dimensions of 39 nm, 68 nm, and 116 nm via single-step self-assembly, which integrated near-infrared imaging and photothermal therapy properties of ICG. Their physiochemical characters were systematically evaluated. In vitro endocytosis, subcellular localization, in vivo metabolic distribution and accumulation were directly observed utilizing the NIR fluorescence of ICG. The cytotoxic effects of different INPs based on drug uptake were also investigated and compared in BxPC-3 cells. Moreover, the photothermal efficacy of three types of INPs to BxPC-3 xenograft tumors was evaluated in vivo.