Abstract
In this mini review, we highlight advances in the last five years in light-activated cancer theranostics by using hybrid systems consisting of transition metal complexes (TMCs) and plasmonic gold nanostructures (AuNPs). TMCs are molecules with attractive properties and high potential in biomedical application. Due to their antiproliferative abilities, platinum-based compounds are currently first-choice drugs for the treatment of several solid tumors. Moreover, ruthenium, iridium and platinum complexes are well-known for their ability to photogenerate singlet oxygen, a highly cytotoxic reactive species with a key role in photodynamic therapy. Their potential is further extended by the unique photophysical properties, which make TMCs particularly suitable for bioimaging. Recently, gold nanoparticles (AuNPs) have been widely investigated as one of the leading nanomaterials in cancer theranostics. AuNPs—being an inert and highly biocompatible material—represent excellent drug delivery systems, overcoming most of the side effects associated with the systemic administration of anticancer drugs. Furthermore, due to the thermoplasmonic properties, AuNPs proved to be efficient nano-sources of heat for photothermal therapy application. Therefore, the hybrid combination TMC/AuNPs could represent a synergistic merger of multiple functionalities for combinatorial cancer therapy strategies. Herein, we report the most recent examples of TMC/AuNPs systems in in-vitro in-vivo cancer tharanostics application whose effects are triggered by light-exposure in the Vis–NIR region, leading to a spatial and temporal control of the TMC/AuNPs activation for light-mediated precision therapeutics.
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1 Introduction
Over the years, transition metal complexes (TMCs) have attracted growing attention as promising theranostic agents for cancer disease [1, 2]. Since the discovery of the antiproliferative properties of cisplatin in the 1960s [3], platinum-based agents have been widely administered in cancer therapy to treat different types of solid tumors [4], currently covering almost 50% of all the clinically used chemotherapy drugs. The mechanism of action underlying the therapeutic efficacy of the platinum compounds approved by FDA is based on their ability to stably bind the nuclear DNA of cancer cells, preventing their replication [4,5,6,7,8]. Nevertheless, the potential of TMCs in cancer medicine has proved to be much more than as mere chemotherapeutics. The presence of heavy metal atoms introduces attractive chemical and photophysical properties, leading—with the choice of proper ligands and metal ions—to luminescent compounds with high emission quantum yields, tunable emission color in the visible region, long excited state lifetimes and large Stokes shifts, properties very useful in biosensing and bioimaging [9,10,11,12,13]. Because of that, ruthenium [14,15,16,17,18,19,20], iridium [21,22,23,24,25,26,27,28,29] and platinum [30,31,32,33,34,35] complexes have been successfully employed as in-vitro and in-vivo luminescent biolabels. Moreover, as a consequence of the strong spin–orbit coupling due to the presence of the heavy atom, the intersystem crossing processes lead to an efficient population of energetically low-lying triplet excited states, often very close to the excited states of molecular oxygen, with consequent energy transfer processes and generation of singlet oxygen. Accordingly, the last decade has seen a dramatic expansion in the investigation of TMCs as photosensitizers in one- and two-photon photodynamic therapy (PDT) [11, 36,37,38,39,40,41,42,43,44,45]—with the first Ru(II)-based photosensitizer entered into human clinical trials in early 2017 for treating non-muscle invasive bladder cancer [46]. Finally, TMCs can be synthesized by combining different ligands and metal centers offering a wide range of oxidation states, coordination numbers and geometries. This molecular versatility can be employed to design site-specific stimuli-responsive prodrugs [47] and novel multifunctional scaffolds suitable for ‘‘all-in-one” cancer theranostic approaches [1].
Last few years have seen an exceptional growth in research and application of nanomaterials in cancer theranostics [48,49,50]. In this field, gold nanoparticles (AuNPs) have emerged as multifaceted platforms for combinatorial cancer therapy strategies [51,52,53]. Inert and highly biocompatible, AuNPs are—like other nanoscale materials—able to passively accumulate in the tumor site via enhanced permeability and retention (EPR) effect [54,55,56]; moreover, their surface can be easily functionalized with active targeting moieties leading to efficient nanocarriers for target-specific delivery of therapeutic agents [57]. Finally, their physicochemical properties can provide spatio-temporal control over the payloads release through internal (i.e. pH) or external stimuli (i.e. light) [57]. An important physical feature of AuNPs involves the localized surface plasmon resonance (LSPR)[58]. When electromagnetic radiation impinges metal nanoparticles smaller than incident wavelength, the surface electrons undergo a collective coherent oscillation in resonance with the electromagnetic field, causing absorption and scattering of the radiation at the resonant frequency. The latter depends on the size and shape of the nanostructure and generally falls within the Vis–NIR range [58]. As a consequence, plasmonic properties of AuNPs can be properly tuned and engineered changing their morphology [59,60,61,62,63,64]. Noteworthy, the interaction between the plasmonic field—generated by AuNPs—and proximal fluorophores, can tune the molecular luminescence, leading to additional interesting effects [65,66,67,68,69]. Moreover, as a result of the optical energy obtained by the oscillating electrons, metal nanoparticles turn into nano-sources of heat [70, 71]. The latter diffuses away from the lattice via phonon–phonon relaxation, leading to temperature elevation of the surrounding medium which can be exploited to trigger drug payload release [72,73,74,75,76,77,78,79,80] and/or the thermal destruction of cancer cells (photothermal therapy, PTT) [81,82,83,84,85,86,87,88,89,90,91].
Owing to their high atomic number, AuNPs have a strong X-ray absorption cross-section, making them effective radiosensitizers for enhanced radiotherapy (RT)[92] and efficient contrast agents for X-ray computed tomography imaging [51, 52]. Finally, due to their aforementioned light absorption/scattering properties, AuNPs have been extensively investigated as promising contrast agents for photoacoustic and light scattering imaging techniques [93,94,95]. These properties—integrated into a single platform—highlight the great potential of AuNPs in light-mediated cancer theranostics [91] and combinatorial cancer therapy [51], providing the unique opportunity to combine simultaneously various diagnosis and treatment modalities with final synergistic effects and enhanced therapeutic outcome.
The combination of the appealing properties of TMCs and AuNPs is now attracting great attention in the scientific community focused on cancer theranostics. An excellent review has recently summarized progress thus far in the nascent field of TMC/AuNP hybrids, focusing particularly on the synthetic protocols, on the multiple characterization techniques as well as on the potential application in imaging, photodynamic therapy, nonlinear optics and catalysis [96]. Herein, we focus our attention on TMCs—in particular ruthenium, iridium and platinum complexes—that have been in the last five years successfully employed in combination with gold nanostructures for in-vitro/in-vivo cancer photo-theranostics.
2 A winning combination: transition metal complexes@gold nanoparticles (TMC@AuNPs)
To date several studies have been reported concerning the photophysical properties of TMCs attached to AuNPs surface or placed at fixed distances from it [97,98,99,100,101,102]. Depending on the distance, nanoparticle size/shape and extent of the spectral overlap between the TMCs emission band and AuNPs plasmonic band, energy and/or electron transfer processes can take place in TMC@AuNP hybrids, resulting in a quenching of the TMCs radiative deactivation [97,98,99,100,101]. On the contrary, in other cases, an enhancement of the TMCs absorption cross-section [103] or luminescence intensity [102] has been observed.
In this section, we will discuss the most relevant aspects regarding the in-vitro/in-vivo applications of TMC@AuNPs in cancer photo-diagnosis and/or photo-treatment from 2014 to date. We will start focusing on their use in imaging techniques and then in phototherapy treatments, in particular PDT and PTT. Then, their application in chemotherapy and in dual- and triple-modality cancer therapies will be described. All discussed TMC@AuNP systems and related application details are reported in Table 1.
2.1 Imaging in-vitro/in-vivo
The first example of Ru(II) polypyridyl functionalized AuNPs as useful cellular imaging probes was reported by Elmes et al. [121]. The successful combination of AuNPs labelled with a luminescent Ru(II) polypyridyl complex was later explored by Rogers and coworkers [104], reporting an efficient coating method for water soluble AuNPs by using a non-ionic fluorinated surfactant (Zonyl 7950). The selected Ru(II) complex bears two thiol groups to bind the AuNPs surface and a hexyl spacer to distance the ruthenium center from the gold core. The obtained nanospheres Ru(II)@AuNPs – with a diameter of 13 and 100 nm – respectively with 103 and 105 Ru(II) complex molecules per AuNP—are red-emissive with an enhanced luminescence lifetime compared to TMC free molecule. Their potential in cellular imaging was highlighted in A549 human lung cancer cells by using conventional optical microscopy techniques. In particular, due to the strong scattering signal of the gold core, Ru(II)@AuNPs appear as bright spots in the confocal reflection images, whereas confocal luminescence displays the intense emission of the TMC molecules upon excitation at 453 nm. Striking, Ru(II)@AuNPs with a size of 100 nm, have been clear imaged in tumor cells at a single nanoparticle resolution.
A fluorinated surfactant and an Ir(III) complex (IrC6)—bearing 2-(hexylphenyl)-pyridine as cyclometalated ligands and a bipyridine with long legs as ancillary ligand—(Scheme 1 from Ref. [103]) have been used to coat water-soluble 13, 25, and 100 nm-diameter gold nanospheres (AuNP13, AuNP25, and AuNP100) in order to develop novel nanoprobes for two-photon lifetime imaging in cancer cells [103]. The different lifetime range—hundreds of nanoseconds for the Ir(III) complex, tens of picoseconds for the AuNPs—allowed a two-channel detection of IrC6@AuNP in live HeLa cells, monitoring independently the gold scaffold and the TMC signal. The presence of the gold nanostructure led to an increased two-photon absorption cross section in IrC6@AuNP25 with respect to the IrC6 molecule. Noteworthy, taking advantage of the Ir(III) complex luminescence lifetime sensitivity to the cell environment, with values ranging from 450 to 1000 ns, an IrC6@AuNP intracellular localization map was obtained for all nanoparticle sizes investigated (Fig. 7 from Ref. [103]).
Dual-modal phosphorescence/computed tomography (CT) bioprobes were reported by Yu et al. [105]. In particular, a bis(2-(2′-benzothienyl)pyridinato-N, C3′) Ir(III) complex and AuNPs (~ 10 nm-diameter) are both encapsulated within polyiohexol nanoparticles leading to composite nanoparticles (BAPI NPs) with an average size of ~ 50 nm for in-vitro and in-vivo imaging of HeLa cells. AuNPs are used as CT contrast agent and—due to the proximity to the TMC—as metal-enhancement fluorescence effect (MEF) agents, with consequent improvement in phosphorescence imaging (Fig. 1). The average luminescence intensity of the BAPI NPs was 5.85 times higher than that of TMC alone in-vivo. A clear outline of the tumor area after mice injection with BAPI NPs highlighted the excellent CT contrasting ability at low doses. Moreover, since the Ir(III) complex is a hypoxic phosphorescence dye, the tumor showed a distinctly brighter red light than that of other tissues and organs.
2.2 Phototherapy in-vitro/in-vivo
In this section we will focus on the light-activated cancer therapeutic approaches carried out employing TMC@AuNPs nanoplatforms. Initially, we will present treatment modalities based on a single approach or "monotherapy", such as PDT or PTT. Then, we will point out on the unique opportunity to implement an all-in-one TMC@AuNPs formulation—by taking the full advantages of AuNPs and the fascinating properties of TMCs—for combinatorial cancer therapy. Indeed, a new emerging trend in clinical oncology is the combination of two or more treatment modalities—including phototherapies, chemotherapy, radiotherapy – in order to exploit their cooperative interactions, resulting in a stronger therapeutic efficacy than that observed using separately every single treatment [51].
2.2.1 Monotherapy
2.2.1.1 PDT/imaging
As aforementioned, a single TMC molecule can act simultaneously as imaging probe and PDT agent. In this frame, our group presented the new combination Ru(II) polypyridyl complexes/gold silica-based nanoparticles (Ru1@GSNP and Ru2@GSNP), as promising nanomaterial for application in imaging and phototherapy [106]. TMCs—encapsulated in the polysiloxane matrix of 50 nm core–shell nanospheres—displayed singlet oxygen generation ability and luminescence properties in the red region of the electromagnetic spectrum. The light exposure of murine mammary adenocarcinoma (TS/A-pc) cells—after incubation with Ru1@GSNP—triggered a remarkable photodynamic activity of the functionalized nanoparticles and a higher inhibition efficiency of the tumor cells proliferation compared with the TMC alone. Moreover, their intrinsic phosphorescence allowed the localization into the TS/A-pc cytosol by fluorescence microscopy, configuring the nanostructures as multifunctional nanoplatforms for theranostic purposes.
2.2.1.2 PTT/imaging
Plasmonic structures at the nanoscale exhibit the renowned ability to transduce the absorbed radiant energy into heat, leading to a local temperature increase. Zhang and coworkers [107] reported an unexpected high photothermal conversion efficiency of gold nanospheres upon grafting with two-photon luminescent Ru(II) polypyridyl complexes. The authors prepared three samples of grafted nanoparticles differed in the distance between the Ru(II) center and the gold surface, and explored how the two-photon luminescence and PTT efficiency changed with the distance. The luminescence was partly quenched due to an energy transfer process from the TMC to the AuNPs depending on the distance from the gold core. The best dual functional nanoparticles of this study was successfully used for real-time luminescent imaging-guided PTT in HeLa cells. The results showed that this sample has a great PTT effect in living cells markedly higher than that of AuNPs, which only displayed a weak PTT effect. Moreover, in-vivo experiments displayed that its use provided tumor ablation under 808 nm irradiation at a low power density. In another paper, the same authors illustrated the results obtained by modifying the shape of the nanoparticles, functionalizing gold nanorods (AuNRs) and gold nanostars (AuNTs) with the most performing Ru(II) complex (Fig. 1a from Ref. [108]). Due to the photothermal effect, naked AuNRs and AuNTs easily melt into gold spheres. This drawback results in loss of the characteristic near-infrared surface plasmon resonance, limiting their therapeutic application. On the contrary, Ru(II) complex-functionalized AuNRs and AuNTs (AuNRs@Ru and AuNTs@Ru, respectively) displayed higher photothermal stability and photothermal conversion efficiency than naked AuNRs and AuNTs. In-vivo PTT studies on HeLa tumor-xenograft mouse model confirmed the different thermal efficiency. After intratumorally injection and laser irradiation for 5 min at 808 nm (Fig. 7 from Ref. [108]), the authors observed a temperature increase of 3, 13, 13, 23.8 and 22.4 °C, for tumor injected respectively with physiological saline, AuNRs, AuNTs, AuNRs@Ru and AuNTs@Ru. Finally, for the experimental groups treated with AuNRs/AuNTs + laser irradiation only a slight delay of tumor growth was observed with respect to the control groups, whereas the groups treated with AuNRs@Ru/AuNTs@Ru + laser irradiation showed photothermal destruction of tumors and no reoccurrence on day 15 (Fig. 9 from Ref. [108]).
2.2.2 Dual-modal therapy
2.2.2.1 PDT/PTT/imaging
An example of multimodal synergistic approach was recently presented by our group [109]. A core–shell gold–silica nanoplatform has been engineered for simultaneous cellular imaging, photodynamic and photothermal therapies: a cationic phenylpyridinate Ir(III) complex, spectrally resonant with the gold core, was properly chosen as photosensitizer and luminescent probe and then encapsulated within the polysiloxane matrix. The spectral overlap between the emission band of the cyclometalated complex and the gold plasmon resonance, led to a competitive energy transfer process from the molecule to the AuNP. Then, in the implemented nanosystem, the radiant energy absorbed by the TMC is partly transferred to molecular oxygen—generating singlet oxygen (photodynamic effect)—and partly to the gold core, with consequent conversion into heat (photothermal effect). In-vitro photo-cytotoxicity tests on human glioblastoma cells (U87MG) demonstrated a high cytotoxic ability of the nanoplatform, reducing the cell viability to 10% already at very low doses (1 μM). Moreover, due to the luminescence properties of the TMC, fluorescence imaging was used to determine the cellular uptake and intracellular distribution of nanostructures [109].
2.2.2.2 PTT/chemotherapy
Xiong et al. [110] presented a dual therapeutic approach—photothermal therapy and NIR laser-triggered platinum-based chemotherapy—employing hollow gold nanoparticles (HGNPs). They synthesized and characterized cisplatin-loaded HGNPs using a tripeptide, acetyl-Glu-Glu-Cys-NH2 (Ac-EEC), as both Pt(II)-chelating agent and linker to HGNPs (Fig. 2a). Finally, folic acid (F) molecules—conjugated to the gold surface—were used as targeting molecules. The resulting F-Ac-EEC(Pt)-HGNPs nano-carrier system was tested in-vitro on folate receptor-expressing KB cells, with and without laser irradiation at 808 nm, corresponding to the plasmon resonance frequency of gold nanostructures. As clearly shown in Fig. 2b, without laser irradiation F-Ac-EEC(Pt)-HGNPs display a cytotoxic effect against cancer cells due to the intracellular release of the cisplatin molecule by an ion-exchange process. The same nanostructures without the Pt(II) complex, F-Ac-EEC-HGNPs, upon NIR laser irradiation induce a reduction of the cell viability due to the plasmonic-mediated photothermal effects. Finally, F-Ac-EEC(Pt)-HGNPs combined with NIR laser irradiation displayed the greatest effects on cell mortality due to the dual approach—photothermal-chemotherapy—resulting in thermal ablation and rapid release of soluble Pt(II) compounds.
A similar combination TMC@AuNP for in-vitro/in-vivo treatment of cervical cancer has been reported by Guan et al. [111]. The tested nanostructures consist of PEG-coated hollow gold nanospheres (HGNs) loaded with cisplatin. Then, NIR laser irradiation was applied to increase the drug penetration into the tumor tissue and improve its delivery, taking advantage of the photothermal conversion properties of HGNs. In-vitro test showed that the combination cisplatin-PEG-HGNs-808 nm irradiation induces a higher cytotoxicity in HeLa cells respect to the non-irradiated system, with a cell viability after treatment respectively of 20% and 60%. Finally, the formulation cisplatin-PEG-HGNs-808 nm light exposure was found to be the most effective in in-vivo studies, leading to a marked tumor regression in mice.
Feng and coworkers [112] described the synthesis and characterization of gold nanorods (GNRs) coated with thiolated poly(ethylene glycol)-graft-poly(L-glutamic acid) copolymers conjugated with folic acid (FA-GNR). The cytotoxic drug cisplatin was then loaded on FA-GNR via coordination bonds between the carboxylic groups of polypeptide poly(L-glutamic acid) and the platinum atom (FA-GNR@Pt), for targeted photothermal/chemotherapy of triple negative breast cancer (TNBC). The obtained FA-GNR@Pt nanostructures enclose—into one single nanosystem—the photothermal conversion properties of GNRs, the high biocompatibility of poly(L-glutamic acid), the anticancer activity of cisplatin and the tumor targeting ability of folic acid. Relative cell viability of 4T1 cells after incubation with FA-GNR@Pt hybrid nanoparticles and exposed to laser irradiation at 655 nm, was significantly reduced to 10%, whereas the treatment with cisplatin molecules—or with the corresponding nanostructures without the cisplatin component—leads the cell viability to 70% and 30%, respectively, highlighting the higher therapeutic efficiency of the dual chemo-thermal approach compared with the related individual monotherapies. Then, the antitumor efficacy and biosafety of FA-GNR@Pt nanoparticles were evaluated in-vivo on TNBC-bearing mice. In particular, the combination of a systemic administration of FA-GNR@Pt with localized near infrared laser illumination resulted in a complete inhibition of the primary tumor growth and the simultaneous prevention of lung metastasis.
Gao et al. [113] realized a cutting edge dual-drug delivery biomimetic system—based on gold nanorods, doxorubicin and cisplatin—for synergistic chemo-photothermal therapy. The surface of the nanorods was first modified with hyaluronic acid followed by the antitumor drugs incorporation. The obtained nanogel system was cloaked with 4T1 cancer cell membrane in order to improve the interactions with the homotypic cells and thus its targeting ability. The 4T1- hyaluronic acid nanogel—gold nanorod – doxorubicin – cisplatin nanostructure (4T1-HANG-GNR-DC) exhibited a dramatically increased cellular uptake. The high intrinsic photothermal conversion efficiency of the gold nanostructures was used to produced heat and then stimulate the drugs release from the particles after cellular uptake. In-vitro test on 4T1 cells showed that the viability was reduced to less than 6% after incubation with 4T1-HANG-GNR-DC followed by irradiation at 808 nm, a cytotoxic effect higher than that obtained by treating tumor cells only with the chemotherapeutic agents or with the dual-drug delivery system without light exposure. The authors then assessed the in-vivo antitumor efficacy of 4T1-HANG-GNR-DC on mice bearing a 4T1 xenograft mammary tumor; compared with the saline group treatment, the tumor volume was suppressed by 96% after intravenous injection of 4T1-HANG-GNR-DC followed by NIR irradiation.
Shanmugam and colleagues [114] reported a light-responsive dual drugs delivery system—based on gold nanorods (AuNRs) and DNA duplexes—for in-vitro/in-vivo cancer photothermal ablation and combination chemotherapy. In particular, the double stranded DNA—tethered to the AuNRs surface—was loaded with doxorubicin and the Pt(IV) prodrug c,c,t-Pt(NH3)2Cl2(OOCCH2CH2COOH)2, the latter in turn conjugated with folic acid by amide binding in order to improve the nanoplatform targeting ability towards cancer cells. It is generally known that Pt(IV) complexes with a high coordination number are kinetically inert and therefore result in fewer side effects compared with Pt(II) species [122, 123]. The NIR-laser irradiation of the developed nanosystem provided hyperthermia and induced the dehybridization of the duplex DNA with consequent chemotherapeutic drugs release. Then, the Pt(IV) prodrugs—inside the cancer cells—were reduced by physiological reductants (e.g. ascorbic acid or glutathione) into their cytotoxic and hydrophilic Pt(II) derivative. In-vitro studies on HeLa cells showed significant cell toxicity after incubation with the nanoplatform followed by irradiation at 808 nm and in-vivo experiments on xenografted mouse tumor model confirmed its therapeutic efficacy.
Shi et al. [115] successfully conjugated PEGylated core–shell Pd@Au nanoplates with the same above-mentioned Pt(IV) prodrug c,c,t-Pt(NH3)2Cl2(OOCCH2CH2COOH)2, obtaining a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. Core–shell Pd@Au nanoplates consist of ultrathin palladium nanosheets on whose surface, gold was successfully grown. The obtained bimetallic nanostructures displayed an intense surface plasmon resonance peak in the NIR region, making them excellent photothermal agents. The NIR irradiation not only enables Pd@Au-PEG-Pt to generate heat for killing cancer cells, but also promotes the release and the chemical reduction of the Pt(IV) prodrug by the bio-reductant ascorbic acid. In in-vitro experiments, Pd@Au-PEG-Pt under irradiation at 808 nm exhibited a higher cytotoxicity on HeLa, QGY-7703 and QSG-7701 cell lines compared with cisplatin. The photo-treatment of mice bearing S180 tumors after Pd@Au-PEG injection resulted in a complete tumor tissue destruction without recurrence, highlighting that—compared with PTT or chemotherapy alone—combined photothermal-chemotherapy displayed a synergistic effect in improving the therapeutic outcome.
2.2.2.3 PTT/chemotherapy/imaging
Zhang et al. [116] synthesized cisplatin-loaded gap-enhanced Raman tags (C-GERTs) for intraoperative real-time Raman detection and chemo-photothermal therapy of disseminated ovarian microtumors. C-GERTs consists of a gold core and a thin gold shell separated by and internal sub-nanometer gap containing 1,4-benzenedithiol Raman reporters, and an external mesoporous silica layer, with cisplatin molecules loaded into the pores (Scheme 1 from Ref. [116]). The developed nanosystem showed numerous advantages: 1) photothermal properties; 2) “fingerprint” Raman signal from the molecules inside the nanogaps, strongly enhanced by the presence of the gold core–shell nanostructure; 3) biocompatibility of the external silica layer, additionally loaded with a chemotherapeutic drug. In-vitro studies on SKOV3 cells revealed that after treatment with C-GERTs + laser irradiation at 808 nm, almost 100% of tumor cells were killed by chemo-photothermal synergistic therapy. Moreover, the authors reported in-vivo intraoperative real-time Raman detection and treatment of disseminated ovarian microtumors. Mice—24 h after C-GERTs injection—underwent aseptic laparotomy surgery and Raman signals of C-GERTs at 1055 and 1555 cm−1 were instantly and easily detected from various tumor size (0.1–0.7 cm in diameter) (Fig. 3a–3c from Ref. [116]). Then, they performed real-time photothermal therapy on the positive Raman locations. In-vivo therapeutic effects after intraoperative chemo-photothermal treatment with multifunctional C-GERTs, showed a near complete elimination of tumors and suppression of regrowth, with a survival rate in SKOV3 mice of 100% during the observation period (Fig. 5e from Ref. [116]).
Another example of image-guided combined chemo-thermal therapy was reported by Zhang et al. [117]. The authors developed a theranostic platform (RGD-IPt-PDA@GNRs) based on polydopamine (PDA)-coated gold nanorods (GNRs), loaded with the anticancer drug cisplatin and labeled with the radioisotope iodine-125. Arginine-glycine-aspartic acid (RGD) peptide was conjugated on the GNRs surface to specifically target tumor angiogenic vessels. Chemo-photothermal therapy effects were evaluated in-vitro on H1299 cells after incubation with RGD-IPt-PDA@GNRs followed by light exposure at 808 nm, revealing a strong decrease in cell viabilities. Then, tumor-bearing mice were injected intravenously with the nanoplatform and single photon emission computed tomography and high-resolution photoacoustic imaging were used to detect RGD-IPt-PDA@GNRs tumor accumulation and angiogenic vessels, confirming that RGD-IPt-PDA@GNRs specifically addressed the latter. Finally, in-vivo studies displayed chemo-photothermal synergistic therapeutic effect on H1299 bearing mice, leading to tumor ablation without relapse.
Yu et al. [118] presented the first example of a combination Ir(III) complex/gold nanomaterials for TNBC multi-modal imaging and synergistic photothermal-chemotherapy. The anticancer [Ir(thp)2phen]+PF6− compound was loaded on gold nanostars (GNS) (Fig. 3a), that due to their branched structure exhibited a plasmonic resonance peak at 808 nm and consequent photothermal conversion ability in the NIR region. In order to enhance the targeting ability against the urokinase-type plasminogen activator receptor overexpressed by malignant cancer cells, the GNS@Ir nanoplatform was functionalized with polyetherimide-AE105 peptide conjugate (Fig. 3a). The resultant GNS@Ir@P-AE105 nanostructure showed an efficient MDA-MB-231 cell uptake and selectivity, a NIR laser controlled release of the TMC, an excellent photothermal/photoacoustic/X-ray computed tomography imaging ability and a synergistic photothermal and chemotherapeutic effect on MDA-MB-231 cells (Fig. 3b). In particular, the IC50 of GNS@Ir@P-AE105 reduced about 10 times compared with that of the Ir(III) complex or GNS used individually, whereas the in-vivo investigation on MDA-MB-231 tumor-bearing mice—after intratumoral injection of GNS@Ir@P-AE105 followed by NIR laser irradiation—revealed an almost complete tumor regression.
2.2.3 Tri-modal therapy
2.2.3.1 PDT/PTT/chemotherapy
Luo and coworkers [119] developed a highly integrated nanocomposite based on mesoporous silica-coated gold nanorods (MSGNR) for tri-synergistic tumor therapy. The photosensitizer Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) was loaded within the porous structure of the silica shell. The polysiloxane surface was functionalized with β-cyclodextrin (β-CD) molecules used as “gatekeepers” to block the premature release of entrapped AlPcS4 and immobilized on MSGNR via a redox-cleavable Pt(IV) complex—derivative of cisplatin—leading to a redox-responsive drug delivery system. In particular, the linker Pt(IV) prodrug c,c,t-Pt(NH3)2Cl2(OOCCH2CH2COOH)2 is conjugated to the amine groups of MSGNR-NH2 and mono-6-ethylenediamine-β-CD by amide bonds. Finally, adamantane (Ad) conjugated poly(ethylene glycol) (Ad-PEG) and lactobionic acid (Ad-LA) were linked on the β-CD through host–guest interaction to promote long term circulation and tumor targeting, respectively. The obtained nanocomposite exhibited very efficient tumor cell selectivity and responsiveness to the intracellular reducing environment triggering the drugs release (AlPcS4 and cisplatin). Under dual light irradiation (808 and 660 nm), the high photothermal conversion—intrinsic to gold nanostructures—and ROS (i.e. Reactive Oxygen Species) generation—due to the photosensitizer activation—led to remarkable HepG2 cancer cells death with only 8% cells survival, strongly highlighting the advantage of the triple-combination therapy. In-vivo experiments carried out on HepG2 tumor-bearing nude mice also revealed the improved tumor accumulation of the nanosystem as well as the higher tumor growth inhibition compared to other treatments groups.
2.2.3.2 PTT/chemotherapy/radiotherapy
A multimodal synergistic cancer therapy approach has also been reported by Mirrahimi et al. [120]. The authors developed a thermo-responsive and radiosensitizing nanoplatform (ACA) by incorporating gold nanospheres and cisplatin into alginate hydrogel to combine chemotherapy, radiotherapy and photothermal therapy. Alginate was used as polymeric carrier for delivery of AuNPs and cisplatin, where gold nanostructures were employed for enhanced radiotherapy and laser-induced photothermal therapy. The antitumor activity of ACA—upon irradiation at 532 nm and 6 MV X-ray—was evaluated in-vivo on murine CT26 colon adenocarcinoma model. Compared to dual-therapy treatment groups—thermo-chemo therapy (ACA + laser)—chemoradiation (ACA + RT)—and thermo-radio therapy (alginate coated AuNPs + laser + RT), trimodal thermo-chemo-radio therapy (ACA + laser + RT) exhibited the most pronounced antitumor efficiency, with a complete tumor eradication and no evidence of relapse during the 90-days follow up period.
3 Conclusions
In this review, we summarized the recent advances in cancer photo-theranostics by using the hybrid combination transition metal complexes/gold nanoparticles as light-triggered therapeutic/diagnostic agents. The main objective was to highlight—going through the several examples reported—the emerging role of TMC@AuNPs nanomaterials in the cutting-edge field of simultaneous diagnosis and therapy of cancer, providing the opportunity to easily tune their properties by properly coupling plasmonic AuNPs—of a specific shape/size—with TMCs having a particular metal center and/or ligands. Certainly, the strength of both components—TMCs and AuNPs—is their ability to interact with the Vis–NIR light radiation, resulting in exclusively light-mediated and then highly localized treatments. As well, the tumor-selective approach can further improved by functionalizing the nanostructures surface with ligand motifs to specifically target cancer cells. The hybrid combination provides the unique opportunity to confine in a single nanostructure a wide range of treatment strategies—i.e. chemotherapy, radiotherapy, photodynamic/photothermal therapies—and to exploit the cooperative interactions between them, resulting in a stronger efficacy than that observed using separately every single therapeutic approach. Cisplatin derivatives and Pt(IV) pro-drugs are well known as chemotherapeutic agents and combined with light-responsive AuNPs can lead to efficient photo-induced drug delivery systems with synergistic therapeutic effects; Ir(III) and Ru(II) complexes exhibit electronic excited states with an energy suitable to promote efficient energy transfer processes towards molecular oxygen and/or plasmonic AuNPs, resulting in photodynamic and photothermal effects. Finally, the intrinsic luminescence of TMCs provides the opportunity to use TMC@AuNPs nanosystems also in fluorescence bioimaging, whereas the presence of AuNPs makes them efficient contrast agents for X-ray computed tomography, photoacoustic and light scattering imaging techniques. Based on the multifaceted advantages, we can certainly expect that the winning combination transition metal complexes/gold nanoparticles will be widely explored in the near future affording significant opportunities in the cancer theranostics field.
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Ricciardi, L., La Deda, M. Recent advances in cancer photo-theranostics: the synergistic combination of transition metal complexes and gold nanostructures. SN Appl. Sci. 3, 372 (2021). https://doi.org/10.1007/s42452-021-04329-6
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DOI: https://doi.org/10.1007/s42452-021-04329-6