Hyaluronic acid and vitamin E polyethylene glycol succinate functionalized gold-core silica shell nanorods for cancer targeted photothermal therapy

Highlights

• Functionalization of gold-core silica shell nanorods with hyaluronic acid and TPGS.

• The HA and TPGS improved the nanorods hemocompatibility and targeting capacity.

• The nanorods targeted photothermal effect eradicated the HeLa cancer cells.

Abstract

Gold-core mesoporous silica shell (AuMSS) nanorods unique physicochemical properties makes them versatile and promising nanomedicines for cancer photothermal therapy. Nevertheless, these nanomaterials present a reduced half-life in the blood and poor specificity towards the tumor tissue. Herein, d-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and Hyaluronic Acid (HA) were combined for the first time to improve the AuMSS nanorods biological performance. The obtained results revealed that AuMSS surface functionalization induced the surface charge neutralization, from -28 ± 10 mV to −3 ± 5 mV and −10 ± 4 mV for AuMSS-TPGS-HA (1:1) and (4:1) formulations, without impacting on nanomaterials’ photothermal capacity. Moreover, the AuMSS functionalization improved the nanomaterials hemocompatibility and selectivity towards the cancer cells, particularly in the AuMSS-TPGS-HA (4:1) formulation. Furthermore, both formulations were able to mediate an on-demand photothermal effect, that induced the HeLa cancer cells death, confirming its potential for being applied as targeted multifunctional theragnostic nanomedicines.

Introduction

In recent years, photothermal therapy mediated by nanomaterials has captured the researchers’ attention as an efficient stand-alone anticancer therapeutic approach [1,2]. For this purpose, the nanomaterials must be able to convert the energy of the irradiating light into heat, which combined with its innate capacity to accumulate in the tumor region originates a localized hyperthermia that leads to the cancer cells death [3,2,4]. In this field, the nanomaterials’ responsiveness to near-infrared (NIR) light (i.e. wavelengths in the 750−1100 nm region) is paramount for avoiding the radiation interaction with the biological constituents [5]. Therefore, the photothermal therapy mediated by nanomaterials provides a high spatial and temporal control over the cancer treatment with minimal invasiveness and side effects [6]. Several types of nanomaterials have already been tested as photothermal agents such as those based on gold, carbon (e.g. carbon nanotubes, nanographene oxide), and copper [[7], [8], [9]]. Among them, gold nanoparticles are one of the most explored for photothermal applications due to their tunable optical properties [6,10]. The gold nanoparticles’ surface plasmon resonance phenomenon allows the fine-tuning of its absorption peak to the near infra-red (NIR) region of the spectra by changing the nanoparticle shape or dimensions [11,12]. Besides that, gold nanoparticles can also improve the tumor imaging through computed tomography and magnetic resonance, which allows the real-time monitoring of the therapeutic response and the nanoparticles’ traffic in the human body [11,13,14]. Nevertheless, the application of bare gold nanoparticles in photothermal applications is limited by the particle’s reshaping phenomena when exposed to high-intensity radiations [15]. Further, gold nanoparticles are prone to interact with compounds containing thiol or disulfide groups, which facilitates their opsonization and consequent removal from the blood circulation [[16], [17], [18]]. To overcome these limitations, researchers have been exploring the gold nanoparticles surface modification with organic and inorganic materials, such as polymers (e.g. poly(N-isopropylacrylamide) and polyethylene glycol) and mesoporous silica [[19], [20], [21]]. In particular, the addition of an optically transparent (NIR), biocompatible, and stable mesoporous silica shell improves the stability of the gold nanoparticles without impacting its photothermal potential [22,23]. Further, the mesoporous silica also limits/avoids the gold-core degradation under irradiation with NIR light and has a large surface area that can be modified with functional groups for increasing the half-life in the blood and tumor accumulation [[24], [25], [26]]. Such prompted the application of gold-core silica shell (AuMSS) nanoparticles in cancer photothermal therapy (PTT), particularly those with a rod-like morphology [[27], [28], [29], [30], [31]].

In this work, AuMSS nanorods were functionalized with hyaluronic acid (HA) and d-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) for the first time to create a tumor-targeted photothermal nanomedicine. Hyaluronic acid is a polysaccharide, composed of repeating glucuronic acid and N-acetyl-glucosamine units, that display a biocompatible, biodegradable, and non-immunogenic profile [32]. Moreover, HA is a ligand for the CD44 receptor, which is highly expressed in different cancer cells. Additionally, high molecular weight HA has anti-angiogenic and immunosuppressive properties as well as present anticancer activity [33,34]. On the other hand, TPGS is a FDA and EMA approved PEGylated derivative of vitamin E, that has been used to prolong the blood circulation time, improve cellular uptake, and enhance the solubility of various drugs [[35], [36], [37], [38]]. Further, TPGS can also inhibit the P-gp efflux pumps and provoke a decrease in the BcL-2 and Survivin levels by preventing the Akt phosphorylation in cancer cells [39,40]. The functionalization of the AuMSS nanorods with different ratios of HA and TPGS was achieved using a post-synthesis condensation strategy. Moreover, the nanoparticles' physicochemical properties and cytocompatibility were characterized to find the most promising formulation for being applied in the cancer PTT.