Elsevier

Pharmacological Research

Volume 143, May 2019, Pages 178-185
Pharmacological Research

A thermo-responsive alginate nanogel platform co-loaded with gold nanoparticles and cisplatin for combined cancer chemo-photothermal therapy

https://doi.org/10.1016/j.phrs.2019.01.005Get rights and content

Abstract

The current interest in cancer research is being shifted from individual therapy to combinatorial therapy. In this contribution, a novel multifunctional nanoplatform comprising alginate nanogel co-loaded with cisplatin and gold nanoparticles (AuNPs) has been firstly developed to combine photothermal therapy and chemotherapy. The antitumor efficacy of the as-prepared nanocomplex was tested against CT26 colorectal tumor model. The nanocomplex showed an improved chemotherapy efficacy than free cisplatin and caused a significantly higher tumor inhibition rate. The in vivo thermometry results indicated that the tumors treated with the nanocomplex had faster temperature rise rate under 532 nm laser irradiation and received dramatically higher thermal doses due to optical absorption properties of AuNPs. The combined action of chemo-photothermal therapy using the nanocomplex dramatically suppressed tumor growth up to 95% of control and markedly prolonged the animal survival rate. Moreover, tumor metabolism was quantified by [18F]FDG (2-deoxy-2-[18F]fluoro-D-glucose)-positron emission tomography (PET) imaging and revealed that the combination of the nanocomplex and laser irradiation have the potential to eradicate microscopic residual tumor to prevent cancer relapse. Therefore, the nanocomplex can afford a potent anticancer efficacy whereby heat and drug can be effectively deliver to the tumor, and at the same time the high dose-associated side effects due to the separate application of chemotherapy and thermal therapy could be potentially reduced.

Graphical abstract

A newly developed thermo-sensitive nanogel platform for combined cancer chemo-photothermal therapy

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Introduction

Despite intensive efforts to achieve an ideal strategy for cancer treatment, this disease still remains a serious health concern worldwide. Traditional cancer therapy methods including surgery, chemotherapy and radiotherapy have their own disadvantages which cannot yield satisfactory therapeutic outcome. In many cancer cases, complete resection of the tumor lesions is often impossible since they are intertwined with normal tissues [1]. Chemotherapy encounters with serious limitations of drug resistance as a result of repeated drug administration as well as adverse side effects due to unwanted accumulation of anticancer drug in healthy tissues [2]. Likewise, radiotherapy is currently insufficient to destroy radioresistant hypoxic tumors and is also associated with radiation-induced side effects [3].

It is generally proved that the effect of certain treatments can be enhanced when combined with other modalities. Accordingly, a new trend is being emerged in clinical oncology to employ the combinatorial cancer treatment strategies in order to exploit the synergistic interactions that occur among different treatments, resulting in much stronger therapeutic effect than the separate use of individual therapies [4,5]. For example, hyperthermia has been widely utilized as an adjunct therapy to increase the tumor cells sensitivity to anticancer drug and X-ray radiation, thus potentiating the cytotoxic effects of chemotherapy and radiotherapy [6]. Therefore, the design and synthesis of hybrid nanocomposites that integrate various therapeutic functions into a single platform have recently attracted increasing interest for simultaneous delivery of multiple treatments to the tumor [7].

Recently, gold nanoparticles (AuNPs) have been widely considered as one of the leading nanomaterials for combinatorial cancer therapy [8]. Owing to their inherent bioinertness, high surface area-to-volume ratio and versatile surface chemistry, AuNPs have the primary prerequisites to be used as an ideal candidate for delivery of various payloads such as gene, protein, and anticancer drug [9,10]. Incorporation of anticancer drugs with AuNPs may improve their bioavailability, solubility and stability. Moreover, AuNPs by taking the advantage of the enhanced permeability and retention (EPR) effect can increase the tumor accumulation of drugs, thus affording a unique opportunity for increasing therapeutic efficiency while reducing normal tissue cytotoxicity [11]. On the other hand, owing to their photoresponsive properties, AuNPs have exhibited great potential in photothermal therapy, where the interaction between incident laser light and AuNPs efficiently generates a localized heating for thermal ablation of the tumor [[12], [13], [14]]. This way, AuNPs can promote the efficiency of conventional laser hyperthermia through localizing the thermal damage to the tumor site while keeping the collateral tissues safe.

Given the fact that hyperthermia can increase the sensitivity of cancer cells to chemotherapy drugs through various mechanisms, the combination of these two modalities (thermo-chemotherapy) has been developed to enhance the efficiency of cancer treatment [15]. The photothermal effect of AuNPs along with their potential in drug delivery make this nanomaterial a unique platform for combined thermo-chemotherapy of cancer. In the present study, we have developed a novel nanocomplex comprising alginate nanogel co-loaded with cisplatin and AuNPs (abbreviated as ACA) for combined chemo-photothermal therapy. To this end, the in vivo antitumor efficacy of this nanocomplex was assessed on BALB/c mice bearing CT26 colorectal tumor model in the presence of 532 nm laser light.

Section snippets

Materials

ACA nanocomplex (NB-NC-100) was prepared in R&D department of Nanobon Company (Tehran, Iran). Fetal bovine serum (FBS) was purchased from Gibco® (USA). Roswell Park Memorial Institute (RPMI) 1640 cell culture medium, penicillin-streptomycin, trypsin-ethylene diamine tetra acetic acid (EDTA) were purchased from the Sigma-Aldrich Company (USA). All mentioned materials were used for cell culture experiment. Hydrogen tetrachloroaurate (III) trihydrate, ACS, 99.99% and Alginic acid sodium salt

Characterization of ACA nanocomplex

The TEM image of the nanocomplex is shown in Fig. 1a wherein AuNPs can be seen as black spots, which are coated by alginate hydrogel. The hydrodynamic diameter of ACA nanocomplex measured by DLS analysis was in the range of 20–80 nm, with the highest frequency around 44 nm and the polydispersity index (PDI) value of 0.38 that ensures moderate monodispersity in aqueous solution (Fig. 1b) [18]. The Zeta potential of ACA nanocomplex was -35.1 mV that proves the good stability of the nanocomplex (

Discussion

Recent years have seen remarkable evolution in the design and application of numerous nanomaterials in cancer nanotechnology. AuNPs with a number of physical properties have been the subject of intensive research in biomedical applications especially cancer diagnosis and therapy [[19], [20], [21]]. In recent years, we have conducted numerous researches in the area of cancer nanotechnology with the special focus on AuNPs [[22], [23], [24], [25], [26], [27], [28], [29]]. In this regard, the

Conclusion

The aim of this study was to develop an efficient strategy for concurrent delivery of heat and drug to the tumor by taking the advantages of nanotechnology in order to achieve synergistic therapeutic outcomes. Aside from the improved chemotherapy efficacy than free drug administration and the good light-to-heat conversion property, the nanocomplex developed herein in combination with 532 nm laser irradiation dramatically inhibited tumor growth and efficiently removed microscopic residual tumor.

Conflict of interest

Non to be declared.

Acknowledgments

All supports received from IUMS and ZaUMS are acknowledged. The authors also express their gratitude to the TUMS Pre-Clinical Core Facilities (TPCF), Tehran, Iran, for providing animal imaging and image processing services for this study.

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