Texaphyrin: From molecule to nanoparticle

Coordination Chemistry Reviews xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Coordination Chemistry Reviews journal homepage: www.elsevier.com/locate/ccr

Review

Texaphyrin: From molecule to nanoparticle Joseph M. Keca a,b, Gang Zheng a,b,c,d,⇑ a

Princess Margaret Cancer Centre and Techna Institute, University Health Network, M5G 2C4, Canada Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, M5S 3M2, Canada c Institute of Biomaterials and Biomedical Engineering, University of Toronto M5S 3G9, Canada d Department of Medical Biophysics, University of Toronto, M5G 1L7, Canada b

a r t i c l e

i n f o

Article history: Received 28 June 2017 Received in revised form 28 August 2017 Accepted 30 August 2017 Available online xxxx

a b s t r a c t In the present review, we present the history and future of texaphyrins, pentaaza Schiff base macrocycles with an expanded 5-coordination sphere, possessing chelation prowess of 24 different stable 1:1 complexes. Intrinsically unique photophysical and magnetic properties of metallotexaphyrins have enabled a broad spectrum of applications, resulting in multiple clinical phase trial evaluations of these compounds. The combination of texaphyrins with nanotechnology underscores the promising future of these materials, which aims to resolve inherent limitations of molecular counterparts in a nanovehicle. Ó 2017 Elsevier B.V. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Porphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Texaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Synthetic strategies of texaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Core building blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Synthesis of texaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Metalation of texaphyrins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Functionalization capabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Influence of metal ions on texaphyrin properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. General photophysical attributes of metallotexaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Lanthanide and transition metals influence on photophysical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Lanthanide metallotexaphyrins attributes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Other metallotexaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Expanded coordination sphere . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Clinical evaluations of texaphyrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Motexafin gadolinium (MGd) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Motexafin lutetium (MLu) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Texaphyrins in nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Inorganic matrices. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Liposomal delivery vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Texaphyrins as nanoparticle building blocks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

⇑ Corresponding author at: Princess Margaret Cancer Centre and Techna Institute, University Health Network, M5G 2C4, Canada. E-mail address: [email protected] (G. Zheng). https://doi.org/10.1016/j.ccr.2017.08.026 0010-8545/Ó 2017 Elsevier B.V. All rights reserved.

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1. Introduction The coordination chemistry of macrocyclic compounds has enabled a broad spectrum of applications unattainable through the usage of free metal ions. Macrocycles are synthetic or natural polydentate ligands, with donor metal atoms incorporated into a cyclic backbone, with or without ligands attached to it. Generally, they contain at least three donor atoms with a minimum ring size of nine atoms [1]. Some of the first examples of metal complexes of macrocyclic ligands were found in the naturally occurring tetrapyrrolic porphyrin class of compounds, such as the ironcoordinating heme proteins [2]. Additional examples include the manganese chlorin complex found in chlorophyll, as well as the cobalt-corrin complex found in vitamin B12, underscoring the pivotal role of metallo-macrocyclic complexes in nature [3,4]. 1.1. Porphyrins The unique and vast chelation capability of porphyrins has resulted in a concerted research effort into the utilization and application of these characteristics, with dozens of reported metalloporphyrin complexes (e.g., Li, Be, Na, Mg, Al, K, Ti, Mn, Cu, Co, Fe, Pt, Tm, Yb, and Lu) [5]. In fact, porphyrin complexes from almost every transition metal are known, with a portion of these complexes being fairly stable. However, some metal cations do possess atomic radii too large to sit within the porphyrin core, resulting in the formation of less stable out-of-plane complexes, or sandwich complexes [6]. Another important feature of porphyrins is that the size and geometry of the porphyrin influence the most stable oxidation states of metal cations contained within metalloporphyrins. A prime example of this is Mn(II) porphyrins, where the high-spin Mn(II) is rapidly oxidized to Mn(III) upon exposure to oxygen, due to the smaller Mn(III) cation having greater accommodation to fit within the porphyrin core. As such, maintenance of desirable oxidation states of metal cations in porphyrins is an ongoing challenge. Instead, the attainment of these metalloporphyrin complexes has enabled access into a spectrum of biomedical applications, as near infrared (NIR) fluorescence, magnetic resonance imaging (MRI), X-ray computed tomography (CT), photoacoustic imaging, photodynamic therapy (PDT) and more recently, positron emission tomography (PET) [7–12]. 1.2. Texaphyrins While naturally occurring traditional porphyrins possess an appreciable range of attainable metal coordinations, it pales in comparison with a synthetically designed class of ‘‘expanded porphyrins,” the texaphyrins (Fig. 1) [13]. Developed in the 1980s by the Sessler group, texaphyrins (a name attributed to their resemblance to the five-pointed star in the state flag of Texas) are pentaaza Schiff base tripyrrane-containing macrocycles that resemble traditional porphyrins, however, differ in that they are expanded (a five-coordination sphere attributed to five donor nitrogen atoms vs. four-coordination sphere in traditional porphyrins) [13–15]. The inner coordination core of texaphyrins is approximately 20% larger than that present in porphyrin, with a centre to nitrogen radius of 2.4 Å [16]. Texaphyrins also differ to porphyrins in that the formal charge on the deprotonated texaphyrin ligand is 1 , whereas 2 for a porphyrin, meaning they behave as monoanionic ligands. Finally, incorporating a Hückel aromatic periphery of 22 p-electrons (vs. 18 p-electrons), texaphyrins possess a larger degree of aromatic delocalization. The development and discovery of texaphyrins underscores human innovation and ingenuity to take a product found in nature and improve the fundamental characteristics of it. Texaphyrins exhibit

Fig. 1. General structure of texaphyrins and reported stable 1:1 chelations.

superiority to traditional porphyrins in their ability to form stable 1:1 complexes with a wide variety of metal cations. Currently, texaphyrins have been reported to form 24 stable 1:1 complexes, predominantly with the medically relevant trivalent lanthanide series (Fig. 1). Generally, metallotexaphyrin complexes are stable with the exception of acidic conditions, which promotes the hydrolysis of the macrocycle [14]. Another way in which texaphyrins differ from porphyrins is the extent of their redox potentials. Texaphyrins are in general easier to oxidize, with candidate complexes Gd–Tex (motexafin gadolinium) and Lu–Tex (motexafin lutetium) being much easier to reduce than typical metalloporphyrins [17,18]. While they possess differences, texaphyrins retain the ability to selectively accumulate in tumour tissue while sparing normal tissue, as observed in other porphyrins [19]. 2. Synthetic strategies of texaphyrins 2.1. Core building blocks Despite texaphyrins being architecturally complex, multicomponent macrocycles, the work done by the Sessler group has allowed attainment of these molecules, through the development of a highly modular synthetic pathway. This synthesis is generally based upon two core intermediates; a tripyrrane dialdehyde and an o-phenylenediamine key precursor (Scheme 1). The tripyrrane dialdehyde is generally obtained in a multicomponent synthesis starting from a protected and substituted pyrrole subunit or from an ester functionalized analogue as a precursor to improve water soluble tripyrrane dialdehydes. Condensation of pyrroles gives tripyrrane in excellent yields (>90%). Debenzylation of tripyrrane by catalytic hydrogenation affords diacids in quantitative yields. Given the reactivity of diacids, this compound is reported to be mildly unstable, resorting to the necessity of using these compounds rapidly upon attainment [13]. Through utilization of the Clezy procedure [20], formylation is rapidly achieved, obtaining dialdehyde tripyrrane in high yield. One of the important features of this synthetic strategy for tripyrranes is that it is direct and purely acid catalysed. In comparison with approaches developed before this, tripyrrane skeletons were constructed in multistep, base-catalysed procedures [21,22]. Another and critical feature of this protocol is the suitability for large scale production, which facilitated texaphyrins capacity to translate in the clinic.

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J.M. Keca, G. Zheng / Coordination Chemistry Reviews xxx (2017) xxx–xxx

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Scheme 1. Synthesis of pivotal texaphyrin precursors and texaphyrin macrocycle.

2.2. Synthesis of texaphyrins The dialdehyde tripyrrane key precursor is then combined with a functionalized o-phenylenediamine, to obtain the sp3nonaromatic form of the texaphyrin ligand. As illustrated in Scheme 1, the combination of dialdehyde tripyrrane with a suitable derivatized o-phenylenediamine under acid catalysed conditions of high dilution (i.e. HCl) results in a 1:1 Schiff base condensation between the two to afford the nonaromatic form of the texaphyrin macrocycle in excellent yields (>90%). This protocol exhibits parallel to that developed by the Mertes group [23], the 2:2 condensation of diamines with diformyldipyrranes, for the formation of the alleged ‘‘accordion” macrocycle [24]. 2.3. Metalation of texaphyrins Attainment of the sp3-texaphyrin enables rapid access to a spectrum of metal coordination complexes through a simple and optimized procedure [13,14,25]. The nonaromatic texaphyrin ligand is oxidized accordingly when combined with a suitable metal salt, atmospheric conditions (molecular oxygen), and an

organic base (e.g., triethylamine), resulting in an aromatic metallotexaphyrin complex in moderate to good yields, depending on the metal cation utilized (Scheme 1, with a recent review by Preihs et al. [26] listing both the metal oxidation state and texaphyrin n+ values for metallotexaphyrin complexes) [25]. For the lanthanide(III) series, there is a general trend that the lighter lanthanide cations (La–Pr) produce slightly lower yields of the complex, whereas the heavier lanthanide(III) cations (Nd–Lu) produce slightly higher yields [25]. These lanthanide(III) complex, as well as the first-row transition metal complexes synthesized [Mn (II), Co(II), Ni(II), Zn(II),and Fe(III)], reactions are generally completed within 1–24 h, with the reaction rate depending on the metal cation identity [16,25]. Another general trend for metal chelation rates is the choice of counter-ion in metal salts. For instance, metal nitrate or acetate salts react more quickly than corresponding halides. Despite this modulation of reaction rate, there appears to be no change in overall yield. An important consideration is the presence of chloride ions from either the HCl salt of the sp3-texaphyrin or in potential column chromatography conditions, which have the capacity to exchange for the original anion of the metal salt. Methods have been developed to overcome this

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Scheme 2. Functionalization of texaphyrins through accessible sites.

issue, which involve washing organic solutions of the complex with an aqueous solution of the anion of choice or usage of anion-exchange columns [16]. Examination of the differential rates of reaction for metalation found with various metal cations led to the notion that reduction in the metal cation may influence the rate-limiting oxidation of the sp3-texaphyrin ligand [16]. Work done by the Sessler et al using first-row transition metals attempted to delineate this hypothesis. Comparing lower valent transition metals Ni(II) and Zn(II), to that of a higher valent transition metal, Mn(III), it was found that Ni(II) and Zn(II) salts required 5 and 24 h in the presence of oxygen for reaction completion. However, Mn(III) did not require oxygen to afford its corresponding metallotexaphyrin, Mn (II)–Tex, which was also obtained using Mn(II) salts in equivalent conditions [16]. As such, this established the idea that the metal cation itself can act as an oxidizing agent within the metalation reaction. This idea was further supported by an Fe(III) texaphyrin complex, where usage of Fe(III) nitrate or Fe(II) acetate under oxygen-free conditions leads to observation of a Fe(II)–Tex [16]. An important feature of metallotexaphyrins is that the metal cation is presumed to enhance the stability of the texaphyrin macrocycle [13]. Once formed, metallotexaphyrins are incredibly stable, with the lone exception of acidic conditions, which have the capability of hydrolyzing the texaphyrin macrocycle [14]. This instability is postulated to occur through protonation of the imine nitrogen, followed by hydrolysis and decomposition of the macrocycle ligand. The ability to possess kinetic and thermodynamically stable metal complexes is a highly important capability of metallotexaphyrins that cannot be overlooked. For instance, in the context of MRI contrast agents, the systemic toxicity of these compounds lies within the dissociation of the metal ion from its coordinated macrocyclic complex. The ability of a macrocycle to have strong kinetic and thermodynamic complexes may allow for improved

safety and efficacy in this context of MRI, as well as a plethora of other biomedical applications. As such, metallotexaphyrins unique extreme stability, in combination with attractive characteristics, constituted further investigations into potential applications of these compounds. 2.4. Functionalization capabilities The texaphyrin macrocycle possesses several sites capable of functionalization (Scheme 2). This allows for a wide range of moieties to be attached onto texaphyrins for desirable functions, such as the inclusion of a PEG chain to improve water solubility. To achieve this, modulation of the functional groups of the tripyrrane key precursor can allow synthetic modulations at this site, resulting in a modulated texaphyrin macrocycle. Additionally, ophenylenediamines are capable of a plethora of functional modifications. To this end, texaphyrins have been conjugated to a wide array of molecules, allowing for strategic enhancement and modulation of texaphyrin functionality. This synthetic freedom of texaphyrins enables access to combine texaphyrins with previously known, biologically active compounds, such as platinum-based drugs. Given cisplatin and oxaliplatin being FDA-approved platinum drugs, strategic usage of these particular platinum-based drugs could facilitate faster clinical translation of these compounds. The compounds are typically synthesized through appropriate functionalization of the o-phenylenediamine key precursor, typically consisting of a platinum-coordinating moiety (i.e., malonate). After synthesis of a metallotexaphyrin-platinum coordinating moiety, platinum coordination is attained rapidly. As a representative texaphyrin-platinum conjugate, the synthesis of Gd–Texmalonato-platinum represents a general synthetic strategy for this class of compound. As with previous texaphyrin syntheses, the

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J.M. Keca, G. Zheng / Coordination Chemistry Reviews xxx (2017) xxx–xxx Table 1 Spectroscopic and photophysical data of metallotexaphyrin complexes. Reproduced with permission from Ref. [28]. Copyright 2000 ACS Publications. Electron config Y–Tex Cd–Tex In–Tex Lu–Tex Nd–Tex Sm–Tex Eu–Tex Gd–Tex Tb–Tex Dy–Tex Ho–Tex Er–Tex Tm–Tex Yb–Tex

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4p 4d10 4d10 4f14 4f3 4f5 4f6 4f7 4f8 4f9 4f10 4f11 4f12 4f13

Atomic no.

ionic Radius (Å)

Soret-band (nm)

39 48 49 71 60 62 63 64 65 66 67 68 69 70

1.075 1.1 0.92 1.032 1.163 1.132 1.120 1.107 1.095 1.083 1.072 1.062 1.052 1.042

474 469 471 477 474 474 472 473 473 474 475 474 477 477

Q-band (nm) 736 733 731 730 740 742 740 739 739 737 737 736 733 732

Sessler group developed synthetic strategies for texaphyrinplatinum conjugates that were clinically translatable. The work conducted on the platinum–texaphyrin conjugates underscores the possibility of combining the beneficial characteristics of texaphyrins with other molecular entities, to improve upon the inherent limitations of one or both of the substituents. The synthetic strategy developed for texaphyrins enables access to an endless possibility of texaphyrin-conjugates. 3. Influence of metal ions on texaphyrin properties 3.1. General photophysical attributes of metallotexaphyrins Texaphyrins possess photophysical properties synonymous to that of traditional porphyrins, with a higher-energy Soret-like band at 470 nm, analogous to the 400 nm band of porphyrins. The Soret-like band is accompanied by flanking N- and Q-like bands at higher and lower energies, respectively, with the lower energy Q-band (740 nm) only observed in centrally coordinated metal texaphyrins, offering a qualitative method to observe metal chelation to texaphyrins. Moreover, the Q-band of metallotexaphyrins offers the unique capability of in vivo excitation, as it falls within the near-infrared tissue penetration region. The spectral properties of the Q-like band of metallotexaphyrins possess a steady shift from red to blue (15 nm) as the lanthanide(III) cation progresses from lanthanum to lutetium [26]. This shift in the Q-like is caused by decreasing atomic radii of the metal cations in the lanthanide series, displaying a linear relationship between Q-like band wavelength (nm) and atomic radius [26]. As with many traditional porphyrins, metallotexaphyrins possess the ability to fluoresce, especially those containing diamagnetic cations. Compared to typical porphyrins, the Q-type emission bands are considerably redshifted (>100 nm) and reside further in the near IR region [27]. 3.2. Lanthanide and transition metals influence on photophysical properties Thorough investigations into the influence of large metal cations on the photophysical properties of texaphyrins have been conducted, shedding light on unique excited-state properties of metallotexaphyrins. Evaluation of solution-phase magnetic susceptibilities of metallotexaphyrins containing coordinated paramagnetic and diamagnetic lanthanide(III) and other cations, found that the singlet (1.593–1.638 eV) and triplet excited-state (1.478–1.498 eV) energies were only slightly affected by the choice of coordinated metal species [28]. Conversely, it was found that photophysical parameters that are directly associated with intrin-

Magnetic moment (B.M.)

Fluorescence maxima (nm)

Singlet energy (eV)

FF

– – – – 2.97 ± 0.02 2.43 ± 0.29 3.57 ± 0.11 7.96 ± 0.15 9.24 ± 0.09 10.25 ± 0.10 9.93 ± 0.09 9.33 ± 0.03 8.20 ± 0.01 4.94 ± 0.33

773 770 768 772 757 778 756 768 772 760 770 769 760 757

1.603 1.609 1.613 1.605 1.636 1.593 1.638 1.613 1.604 1.630 1.609 1.611 1.630 1.636

0.04 0.015 0.032 0.015 0.0002 0.0005 0.0006 0.0028 0.0005 0.0004 0.0017 0.0011 0.0009 0.0018

Lifetime (fluor.) (ps)

ISC (109
s

1298 715 1149 414 515 420 288 208 154 99 <100 <100 161 247

0.605 1.48 0.957 1.89 0.819 1.5 2.31 3.77 4.42 15.6 18.3 10.9 9.33 3.17

1

)

sic decay rates (i.e. fluorescence lifetimes) were strongly dependent on the type of coordinated metal cation [28]. It was found that increasing the atomic number in diamagnetic metals (Y, In, Lu, and Cd) leads to shorter fluorescence lifetimes (sfluorescence(YTex) = 1298 ps, sfluorescence(Lu–Tex) = 414 ps, Table 1). As a result, size effects play an important role in lanthanide(III) texaphyrins, with Ref. [28] providing a thorough analysis of this. An expected consequence of increased atomic radii for lanthanide(III) cations is out-of-plane displacement of the coordinated metal core, leading to distortions of the macrocyclic framework. This is observed in texaphyrin complexes containing larger cations (i.e. Gd–Tex and Eu–Tex), with a calculated out-of-plane displacement of 0.60 Å [25,29]. As a result, the macrocyclic coordination sphere and average metal-nitrogen bond length increases, which predictably lowers the potential overlap between metal ion forbitals and the texaphyrin-centred p-system. In earlier works, it was shown that structural and orbital overlap effects impacted the lifetime and reactivity of the one-electron reduced metallotexaphyrin species (M-Tex+), with the authors suggesting this could play a role in modulating the lifetime of the first singlet excited state, S1 [30].

3.3. Lanthanide metallotexaphyrins attributes When comparing the paramagnetic (Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, and Yb) to diamagnetic metallotexaphyrin analogues, it was found that paramagnetic species possess much shorter fluorescence lifetimes (sfluorescence = 99–515 ps), with fluorescence quantum yields (/F = 0.0002–0.0028) that are a minimum of one order of magnitude smaller than those found for analogous diamagnetic species (/F = 0.015–0.04) [28]. A purported rationale for this difference is that the paramagnetic metal centres interact with the excited electron in the p⁄-orbital and, consequently, accelerate the spin-forbidden intersystem crossing between the singlet and triplet excited states [28]. It was also found that the triplet lifetimes and intersystem cross rates depend on the magnitude of the magnetic moment of the metal cation in the paramagnetic complexes. Of the paramagnetic complexes, Ho–Tex and Dy–Tex possess the shortest fluorescence lifetimes and highest intersystem crossing rates, whereas Nd–Tex, Tb–Tex, Er–Tex, and Yb–Tex demonstrated slower rates [28]. Attempts at elucidating the mechanism by which these trends occur were difficult, with initial efforts at creating a correlation between observed dynamics and the number of unpaired electrons at the metal centre failing. While the intersystem crossing rates increase and fluorescence lifetimes decrease with increasing atomic number, Gd–Tex and Tb–Tex complexes challenge this rationale. These complexes, despite having a

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larger number of unpaired electrons, possess slower intersystem crossing rates and longer lifetimes than Ho–Tex or Dy–Tex [28]. Efforts to elucidate the mechanism are ongoing. However, in diamagnetic complexes, the singlet lifetime, triplet lifetime, and intersystem crossing rates instead correlate with the atomic number of the cation. This evidence suggests covalency in the metal–texaphyrin bonding interactions and is substantiated with findings demonstrating a correlation between the magnetic moments of the paramagnetic lanthanide(III) texaphyrin complexes and fluorescence lifetimes, with that of the intersystem crossing rates [28]. The importance of this experimental evidence cannot be overlooked, as it provides strong additional evidence for covalent interactions between the metal f-orbitals and the porbitals of the texaphyrin macrocycle. Comparing complexes with similar magnetic moments but different out-of-plane displacements further strengthens these covalency interactions. Examination of the Gd–Tex/Tm–Tex and Tb–Tex/Er–Tex pairs highlight this, where individual complexes possess similar magnetic moments; however, fluorescence lifetimes, intersystem crossing rates, and triple lifetimes differ significantly between them. The smaller metal cations presumably sit deeper within the plane of the macrocycle, and as such, would be subject to a greater degree of orbital overlap and thus display the fastest deactivation rates [28]. The differences in triplet quantum yields for diamagnetic complexes (Y, In, Lu, and Cd) were shown to correlate strongly with differences in singlet oxygen quantum yield. It was found that the lightest species, Y–Tex, possessed the highest net singlet oxygen quantum yield (/D = 0.54), whereas the heaviest, Lu–Tex (/D = 0.31), produced the lowest. A rather interesting point, considering it is Lu–Tex that was evaluated in clinical trials for photodynamic therapy applications. It is important to note that the observed short lifetimes of the triplet excited states in the paramagnetic series prevent meaningful, rate-determination reaction with molecular oxygen. Despite Eu–Tex and Gd–Tex producing singlet oxygen, their quantum yields pale in comparison with the corresponding diamagnetic complexes examined. The detailed photophysical analyses of the lanthanide(III) series underscore the notion that the nature of the coordinated metal cation contributes little effects to the relative energies of the ground, singlet, and triplet excited states [25,30]. Conversely, the rates of excited state deactivation and quantum yields (fluorescence and triplet) are instead highly dependent on the identity of the metal cation. Given these variables are dependent on the rates of intersystem crossing, and thus spin-forbidden spin interconversion processes, it is evident that both heavy atom and paramagnetic cation effects play a role in the outcome of these parameters.

expected value given the spin 5/2 state [16]. This spin state is synonymous to other 4-coordinate and 5-coordinate Mn(II) porphyrins (high-spin 5/2 state), whereas six-coordinate Mn(II) porphyrin complexes are typically low spin [33]. Co(II) texaphyrins displayed leff = 4.18 lb, consistent with a high-spin (S = 3/2) d7 system [16]. These differ from Co(II) porphyrin, which instead typically exist as low-spin (S = ½) complexes [6]. Ni(II) texaphyrins displayed a spin-only magnetic moment of leff = 2.86 lb, precisely the value for a high spin (S = 1) d8 system. This data suggested that the Ni(II) in texaphyrin is not in a square-planar coordination environmental, typical of Ni(II) porphyrins. Instead, it is possible that the expanded core of texaphyrin is accommodating an octahedral or square-pyramidal geometry. Fe(III) texaphyrins exist as a loxo dimer, with single-crystal X-ray diffraction analysis indicating the face-to-face texaphyrin macrocycles are orientated in a manner so that the benzene-ring portion of one is under the tripyrrolyldimethene portion of the other [16]. With the Fe atoms being displaced slightly out of the plane of the ring (0.112 Å), there is a slight angle between the linear FeAOAFe bond and the equatorial plane of each texaphyrin. The Fe(III) texaphyrin dimer possesses a leff = 6.01 lb per complex, which is lower than the predicted value for two independent Fe3+ high-spin metal centres and is attributed to an antiferromagnetic interaction between bridging Fe(III) cations [16]. To substantiate the electronic assignments made through the analysis of the magnetic moments, electron paramagnetic resonance (EPR) analyses at 4 K of these coordination complexes revealed EPR spectra that agreed closely with these assignments. While the analysis of magnetic moments provided invaluable insight into the electronic assignments of late first row transition metal complexes of texaphyrin, UV–Vis spectroscopic studies highlighted unique photonic properties, unseen with the lanthanide(III) texaphyrin series. Comparing the monomeric transition metal complexes [Mn(II), Co(II), Ni(II), Zn(II), and Fe(III)] to that of the lanthanide(III) texaphyrins, the two series display spectra that are highly similar in shape and intensity [25,29], as well as possessing a physical appearance of intensely coloured green-yellow solutions. Interestingly, the spectra of the late first row transition metal complexes are mainly blue-shifted in comparison with the lanthanide(III) complex series (Fig. 2). This pattern of absorbance is synonymous to that observed in metalloporphyrins, with wellestablished experimental and theoretical work in this field [34]. The positions of the Soret-like and Q-like bands in the late first row transition metal texaphyrin complexes follow a shift that

3.4. Other metallotexaphyrins While the lanthanide(III) series received considerable attention in their evaluations, efforts were made to examine a series of late first-row metallotexaphyrin complexes. For instance, a watersoluble Mn(II) texaphyrin (Mn–Texc+) [31] was found to catalyse the disproportionation of peroxynitrite, a reactive oxygen species implications in the pathogenesis of atherosclerosis, ALS, and cancer [32]. The discovery of this complex supported the notion that perhaps new metallotexaphyrin complexes aside from the wellestablished lanthanide(III) series could possess useful and relevant biological activities. Investigations into the first-row transition metal [Mn(II), Co(II), Ni(II), Zn(II), and Fe(III)] metallotexaphyrins provided valuable information into the structural and electronic properties of these complexes. Manganese is a medically relevant MRI contrast agent, as such, solution magnetic moment determinations were carried out to better understand Mn(II) metallotexaphyrins. An Mn(II) texaphyrin produced a leff = 5.91 lb, an

Fig. 2. UV–vis spectra of inner transition metal–texaphyrin complexes in methanol. Reproduced with permission from Ref. [16]. Copyright 2002 ACS Publications.

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corresponds to the identity of the metal atom, with additional slight dependence solvent choice as well. As a unique complex, the l-oxo-dimer Fe(III) texaphyrin displays hypsochromicity and broadening in its UV–vis spectrum, which is characteristic to what is observed in analogous porphyrin systems [34]. It was also found as a general rule, that regardless of the metal cation or solvent, the use of differentially substituted by electronically similar texaphyrin ligands leads to minor modulations in the Soret-like band (3 nm) and the Q-like band (5 nm), with insignificant change in the extinction coefficient [16]. Solvent effects do play a minor role, however, and must be considered when acquiring UV–vis spectra. For example, the Soret-like band of Mn–Texc shifts from 467 to 461 nm when recorded in CHCl3 vs. H2O. The Q-like band also appears to be influenced, where measurements in CHCl3 result in red-shifting of the band (10 nm) in comparison with H2O. As such, mounting evidence suggests metallotexaphyrins experience a solvachromic effect [35,36], a phenomena characterized with charge-transfer contributions to both the Qband (S0 ? S1 low energy transition) and the Soret band (S0 ? S1 higher energy transitions) in the texaphyrin chromophore [16]. These charge-transfer effects also support the previous notions of covalency in the texaphyrin ring, further strengthening the evidence of covalent bonding between the deprotonated macrocycle and metal cation. For the late first row transition metal complexes [Mn(II), Co(II), Ni(II), Zn(II), and Fe(III)], there appears to be a large 23 nm blue-shift of the Q-like band as the metal moves across the row from Mn(II) to Zn(II). Examinations of the late first row transition metal series singlet and triple lifetimes and fluorescent quantum yields exhibited trends reminiscent to the paramagnetic lanthanide(III) texaphyrins. For instance, in comparison with the diamagnetic Zn(II) complex, the singlet and triple lifetimes of the paramagnetic species were found to decrease by a factor of 5 and 1000, respectively [16]. This reflects photophysical properties displayed in the paramagnetic lanthanide texaphyrins, a trend that is ascribed to the enhancement of internal conversion and intersystem crossing rates [28]. Interestingly, comparing the diamagnetic Zn(II) texaphyrin and Y(III)texaphyrin, the fluorescent quantum yield of the Zn(II) texaphyrin was lower than that found in the Y(III) complex, despite having a lower atomic number and thus reduced heavy atom effect [16]. Additionally, the triplet quantum yield for Zn(II) texaphyrin (0.59) was near identical to that of Y(III) texaphyrin (0.56), while possessing identical singlet oxygen quantum yields (0.54) [28]. To explain this it is thought that there is a higher level of vibration freedom in the Zn(II) texaphyrin, as well it is possible that there is stronger covalent bonding between the metal and texaphyrin macrocycle in the Zn complex, than in other metallotexaphyrin complexes [16]. Another relatively new report of texaphyrin coordination complexes is lead(II) and bismuth(III)–texaphyrins [37]. A single crystal X-ray structure of a Bi(III)–texaphyrin was obtained in a binuclear macrocyclic l-oxo bismuth complex, which at the time was the first structurally characterized complex of its kind. Further to this point, this was the first stacked expanded porphyrin system to be obtained with a texaphyrin and non-transition metal [37]. Another important feature of these Pb(II) and Bi(III)–texaphyrin complexes lies within their potential applications in usage of the radioactive isotopes 212Bi, 213Bi, or 212Pb, as a-core emitters for radiotherapy. 3.5. Expanded coordination sphere One of the most striking features of texaphyrin complexes in late first row transition metals is the observation that their transition-metal cations are preferentially stabilized in a lower oxidation state and overall higher spin state compared to analogous

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porphyrins [16]. This is not entirely depending on the charge of ligand, as seen in the Co(III) oxidation state found in vitamin B12 [38]. As a result, this supports the notion that the larger texaphyrin ligand provides a better ‘‘fit” for larger metal cations. Furthering the comparison to traditional porphyrins, Mn(II) is found to be the preferred oxidation state in the texaphyrin complex, whereas Mn(II) is rapidly oxidized to Mn(III) in porphyrins, eluding to issues of oxidation state control in traditional porphyrins. The observation of the l-oxo-dimer being the preferred form of the Fe(III) complex further supports this notion. These observations, in conjunction with NMR and EPR spectroscopic analyses (in the context of paramagnetic metal cations), suggest that texaphyrin in fact contributes a weaker ligand field and thus less in d–d orbital splitting. Despite the absence of a strong ligand field, this does not prevent the transition-metal cations from exerting a profound effect on the orbital energies of the texaphyrin chromophore [16]. This is reflected in the UV–vis spectra of the late first row transition metal complexes, which display a 23 nm blue shift of the Q-like band when moving from Mn(II) to Zn(II). Similar blue shifts (ca. 8 nm total) are observed in the Q-like and Soret-like bands of the lanthanide(III) texaphyrins, as the series moves from Nd(III) to Lu (III) [28]. The enhanced size complimentary and charge neutralization of the smaller lanthanide cations is believed to contribute to this finding. The capability of texaphyrins to coordinate lanthanide(III) cations, as well as a range of inner transition metals, constitutes it as a macrocycle with one of the broadest coordinative limits known. It can be viewed that the lanthanide(III) cations represent one end of this coordinative limit of texaphyrin, where metal cations reside above the plane of the pentadentate macrocycle. On the opposite end of this coordinative limit lies the late first row transition metal complexes, with Zn(II) being the smallest cation complex, with texaphyrin acting instead as a tridentate ligand. Texaphyrins expanded ligand core results in stabilization of complexes of larger metal centres, lower oxidation states, and of higher overall spin; characteristics unseen in congeneric porphyrin systems. The culmination of texaphyrins unique capabilities and characteristics constituted vast and concerted research efforts into metallotexaphyrin applications, an endeavour that currently continues. 4. Clinical evaluations of texaphyrins The culmination of work performed on the synthesis and fundamental evaluations of texaphyrins led to the assumption that these compounds could serve a role in biomedical applications. While there were a wide array of metallotexaphyrins studied, two lanthanide(III) complexes received immediate attention as the most interesting, Gd–Tex and Lu–Tex. Gadolinium(III) is the single most paramagnetic monoatomic cation known, and thus the formation of a stable complex between Gd(III) and texaphyrin led to the idea that it may possess MRI signal enhancing properties [16,39,40]. Shifting focus to the diamagnetic cation Lu(III), the knowledge of texaphyrins ability to absorb strongly in the tissue transparent region (>700 nm) led to the idea that Lu–Tex may be effective as a photodynamic therapy (PDT) photosensitizer [41,42]. The below sections will highlight the clinical evaluations of the Gd–Tex candidate, motexafin gadolinium, and the Lu–Tex candidate, motexafin lutetium. Table 2 highlights key clinical trials involving motexafin gadolinium and motexafin lutetium. 4.1. Motexafin gadolinium (MGd) Perhaps one of the most thoroughly studied of all metallotexaphyrins, motexafin gadolinium (XcytrinÒ, Pharmacyclics, Inc.)

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Table 2 Key clinical trials involving texaphyrin-based drugs. Study ID; year of registration; country of conduct of study Motexafin lutetium NCT00005067; 2000; United States NCT00005808; 2000; United States NCT00087191; 2004; United States Motexafin gadolinium NCT00003909; 1999; NCT00003409; 1999; NCT00003410; 1999; NCT00003798; 1999;

United United United United

States States States States

NCT00003736; 1999; Canada, United States NCT00006452; 2000; United States NCT00004262; 2000; United States NCT00005065; 2000; United States NCT00022256; 2001; United States NCT00036790; 2002; United States NCT00032097; 2002; United States NCT00054795; 2003; Canada, United States, France, Germany, Netherlands NCT00086034; 2004; United States NCT00076401; 2004; United States NCT00080028; 2004; United States NCT00096837; 2004; United States NCT00080041; 2004; United States NCT00080054; 2004; United States NCT00089284; 2004; United States NCT00134186; 2005; United States NCT00100711; 2005; United States

Sponsors

Disease condition

Phase of clinical trial

National Cancer Institute National Cancer Institute National Cancer Institute

Locally recurrent prostate cancer Cervical intraepithelial neoplasia NSCLC

Phase 1 Phase 1 Registered

National Cancer Institute Jonsson Comprehensive Cancer Center Jonsson Comprehensive Cancer Center Sidney Kimmel Comprehensive Cancer Center University of Pennsylvania Sidney Kimmel Comprehensive Cancer Center National Cancer Institute National Cancer Institute Memorial Sloan Kettering Cancer Center University of Wisconsin, Madison National Cancer Institute Pharmacyclics LLC.

Untreated childhood brain stem glioma Brain and CNS tumours Brain and CNS tumours Pancreatic cancer

Phase Phase Phase Phase

Breast cancer Brain and CNS tumours

Pilot study Phase 1

Supratentorial glioblastoma multiforme NSCLC Glioblastoma multiforme Advanced cancers Brain and CNS tumours Brain neoplasms

Phase Phase Phase Phase Phase Phase

1 1 2 1 1 3

Pharmacyclics LLC. Pharmacyclics LLC. Pharmacyclics LLC. Pharmacyclics LLC. Pharmacyclics LLC. Pharmacyclics LLC. Northwestern University Pharmacyclics LLC. Pharmacyclics LLC.

Non-Hodgkin’s Lymphoma Chronic lymphocytic leukaemia Advanced head and neck cancer Multiple myeloma Breast, ovarian, prostatic, and lung neoplasms Malignant gliomas Non-Hodgkin’s Lymphoma Kidney cancer Chronic lymphocytic leukaemia or small lymphocytic lymphoma Brain metastases Brain, ovarian, prostatic, lung, and gastrointestinal neoplasms NSCLC NSCLC NSCLC

Phase Phase Phase Phase Phase Phase Phase Phase Phase

2 2 1 2 1 1 1/2 2 2

NSCLC Pontine glioma Chronic lymphocytic leukaemia or small lymphocytic lymphoma Glioblastoma multiforme and gliosarcoma Brain and CNS tumours Brain and CNS tumours Kidney cancer

Phase 2 Phase 2 Phase 1/2

Liver cancer

Registered

Non-Hodgkin’s Lymphoma Prostate cancer

Phase 2 Registered

NCT00121420; 2005; Canada, United States NCT00120939; 2005; United States

Pharmacyclics LLC. Pharmacyclics LLC.

NCT00102505; NCT00129844; NCT00373204; Serbia NCT00365183; NCT00387790: NCT00290004;

2005; United States 2005; Canada, United States 2006; United States, Canada, Russia,

Pharmacyclics LLC. Pharmacyclics LLC. Pharmacyclics LLC.

2006; United States 2006; United States 2006; United States

Pharmacyclics LLC. National Cancer Institute Pharmacyclics LLC.

NCT00305864; NCT00514397; NCT00734773; NCT00717587;

2006; 2007; 2008; 2008;

National Cancer Institute Children’s Cancer and Leukaemia Group Northwestern University Abramson Cancer Center of the University of Pennsylvania American College of Radiology Imaging Network Spectrum Pharmaceuticals, Inc American College of Radiology Imaging Network

United States Ireland, United Kingdom United States United States

NCT01082224; 2010; United States NCT01549886; 2012; United States NCT01562223; 2012; United States

underscores the potential of metallotexaphyrins as biomedical agents. Early investigations on MGd were premised on its capability for being MRI detectable, allowing for non-invasive assessment of tissue localization and clearance. After thorough investigations on MGd it was discovered that this compound in fact generates reactive oxygen species (ROS). Initial fundamental studies demonstrated MGd having a greater propensity to be reduced in comparison with typical porphyrins, and as a result can act as a redox mediator producing ROS in the presence of a suitable environmental (e.g., reductants, oxygen). The proposed mechanism by which MGd produces ROS involves an initial step of a 1e acceptance from suitable reducing metabolites (e.g. ascorbate, reduced NADPH, TRXR, GSH, and dihydrolipoate) once in the intracellular environment, thereby resulting in oxidation of these compounds [26]. In vitro studies demonstrated that once texaphyrin accepts an electron, it forms a texaphyrin reduced radical, capable of reacting with molecular oxy-

1 1 1 1

Phase 2 Phase 1 Phase 1 Phase 2 Phase 2

Phase Phase Phase Phase

1/2 2 1 2

gen to form superoxide in a rapid equilibrium process [43]. Once this superoxide is formed, it is rapidly converted into hydrogen peroxide, a potent apoptosis initiator. Another important feature of MGd is its ability to ‘‘sponge up” electrons formed as the result of the interactions of X-rays with water during ionizing radiation [e.g., whole brain radiation therapy (WBRT)]. Since the repair of DNA damage caused by ionizing radiation requires a pool of reducing agents to donate electrons [44], MGd-induced depletion of this pool of substrates thereby diminishes cellular capabilities of DNA repair [45]. Consequently, the combination of X-ray radiation and MGd leads to an augmented concentration of hydroxyl radicals (the higher cytotoxic daughter product formed from the reaction of X-rays with water) under hypoxic conditions [45]. Furthermore, even in the presence of oxygen, this electron capture event produces a metastable reduced MGd radical, which also reacts with molecular oxygen to form the superoxide anion.

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Another proposed mechanism of cellular death by which MGd acts is through the thioredoxin pathway. Investigations have suggested that a primary target of MGd is cytosolic thioredoxin reductase (TrxR1), an important component of the cellular antioxidant system, as well as apoptotic signalling and DNA synthesis [46]. MGd is proposed to inhibit TrXR1 disulphide reductase activity, thereby generating ROS (superoxide and hydrogen peroxide). Additional studies have suggested a relationship between MGd and ribonucleotide reductase (RNR), an enzyme required for DNA synthesis and repair [47–49]. MGd inhibition of RNR is proposed to halt DNA synthesis, DNA repair, and cell growth, thereby inhibiting intracellular pools of dNTPs (required for S-phase DNA synthesis), ultimately increasing the effectiveness of MGd in oncology applications. It has also been proposed that MGd effectiveness in oncology treatment may be due to a proposed mechanism involving its ability to mobilize and release intracellular zinc [50]. This disruptive increase in zinc leads to altered transcription factor activity, cell signalling pathways, and gene expression [51]. In vitro evaluations of MGd in prostate cancer and lymphoma cell lines have supported this causal relationship [50]. Additional mechanisms of actions involving MGd involve MGd facilitating the mitochondrial apoptotic pathway (caspase-dependent) in the HF-1 lymphoma cell line [52]. It was further demonstrated in these studies that MGdinduced apoptosis results in the loss of mitochondrial membrane potential, leading to cytochrome c release and activation of caspase 9 from caspase 8 [52]. The combination of MGd and ionizing radiation produced ROS in the lysosome and mitochondria, thereby triggering apoptosis by the aforementioned mechanisms, where subsequent release of messenger factors induce apoptosis of nearby cells [53,54]. Consequently, MGd in combination with ionizing radiation results in a multi-centre cell killing cascade, which may occur in combination with modulations in cell cycle checkpoint-dependent function [45,51]. This may aid in explaining the observation of little or no activity of MGd in in vivo or in vitro assays but displaying high in vivo activity. Regardless of the mechanism of action proposed for MGd, it is evident through this fundamental and mechanistic preclinical evaluations that MGd possessed significant potential in the field of oncology, thus prompting clinical evaluations of this agent. To this end, it was proposed that MGd could have a role in oncology treatment as a radiosensitizer. One of the main aspects of MGd that constituted it as an ideal candidate as a radiosensitive is its demonstrate ability to selective accumulate in tumour tissue over normal tissue [19]. As a result, motexafin gadolinium developed by the Sessler group was catapulted into clinical study under the banner of Pharmacyclics, Inc. [55,56]. The first Phase I dose escalation study of MGd involved a total of 38 patients with brain tumours, with results demonstrating good tolerability for MGd. The major dose-limiting toxicity of MGd derived from the study using the single dose setting was reversible acute tubular necrosis, with the maximal tolerated single dose found to be 22.3 mg/kg [57]. To assess MGd in the paediatric population, a Phase I study investigated the maximum tolerated dose (MTD) of MGd, involving field radiation therapy for the treatment of paediatric pontine gliomas [58]. A MTD was determined to be 4.4 mg/kg with radiation therapy of 54 Gy administrated in 30 once daily fractions, which established the Phase II dosing regime [51]. The unique and favourable intrinsic properties of MGd have led to its entering of a Phase III clinical trial for patients with brain metastases derived from nonsmall cell lung cancer. Despite observing a delay of neurologic progression in patients who had received MGd and whole brain radiation therapy compared to radiation alone [59], MGd was not approved by the FDA. The conclusion from this study appears to be that MGd is safe (no haematological toxicities) but produces only mild radiation enhancement. Therefore, despite promising

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preclinical results, the implementation of radiation sensitizers, in particular MGd, have had limited clinical success. Perhaps it is possible the combination of texaphyrin and nanotechnology can overcome these inherent limitations, affording the increased efficacy necessary to realize their clinical potential through increased tumour accumulation with the sheer number of MGd delivered in each nanoparticle. 4.2. Motexafin lutetium (MLu) By substituting gadolinium with lutetium, MLu (AntrinÒ Phototherapy) was shown to be a potent singlet oxygen generator, and thus, served a role in photodynamic therapy (PDT). In early pre-clinical models, the effect of MLu and PDT in a normal canine prostate model investigated, showing that MLu in conjunction with PDT leads to inflammation and necrosis, followed by glandular atrophy and fibrosis [60]. In a Phase I trial, MLu was investigated in patients with recurrent prostate cancer. Intravenous administration of MLu (0.5–2 mg/kg) at multiple time points was conducted, where light delivery was subsequently administered. By harnessing the optical properties of MLu (an absorption wavelength of 732 in the tissue transparent region), MLu concentration in human prostates could be measured. In these studies, a significant amount of inter- and intra-patient heterogeneity was discovered, as well as a light penetration depth of 0.4 cm, a value half than what was observed in the canine prostate [60]. Additional studies also observed inter- and intra- patient heterogeneity optical properties in the prostate, before and after PDT application [61– 63]. This variability may cause uncertainty and inconsistency in MLu evaluation, thereby hindering its success in later stage clinical trials. While MLu has not been approved by the FDA, it is evident that MLu is a promising compound with considerable potential in the field of oncology. 5. Texaphyrins in nanotechnology With a large collective effort over the past few decades investigating texaphyrin molecules, from fundamental mechanistic studies to clinical trial evaluations, it was a natural progression to combine texaphyrins with the field of nanotechnology. Nanoparticles have been produced with a range of materials, such as lipids [64], transition metals [65], inorganic salts [66], and even organic macrocycles [67]. As such, the field of nanotechnology offered a new, unexplored realm of possibilities to investigate with texaphyrins. This section will highlight some of the most recent reports of texaphyrins in nanotechnology, a field that is currently ongoing and evolving with new publications, catapulting texaphyrins to the forefront of research once again. 5.1. Inorganic matrices Nanomaterials comprised of inorganic material have been a staple in the field of nanotechnology for the past several decades. It was of no surprise that texaphyrins were combined with the technology of inorganic nanoparticles to create novel multifunctional nanoparticles with unique properties unseen with individual monomers. An example of this is a reported Gd–Tex based dualmodal MRI contrast agent system, a magnetic nanoparticle consisting of a Zn0.4Fe2.6O4 core (diameter of 15 nm), a coated layer of silicon dioxide, and finally Gd–Tex coated to the surface (Fig. 3) [68]. In these termed ‘‘double-effector” nanoparticles, each component possessed strategic properties to create an end-result multifunctional agent capable of T1/T2 MRI contrast imaging and apoptotic hyperthermia. The zinc-doped iron oxide core possessed T2 relaxation (acting as a superparamagnetic nanoparticle), as well as hav-

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Fig. 3. Double-effector nanoparticles and general strategy of utility. (a) ROS generated from nanoparticle sensitize cancer cells for hyperthermia for lower temperatures (43 °C). (b) Synthesis of Gd–Tex MNPs, involving coating with SiO2, followed by amine-functionalization to Gd–Tex using DSS as cross linker. (c) TEM images of (i) core MNPs and (ii) Gd–Tex MNPs. (d) T1 and T2 MR phantom images of GdTx MNPs, GdTx, and MNPs. Reproduced with permission from Ref. [68]. Copyright 2012 John Wiley & Sons, Inc.

ing the capability of highly efficient heat-generation under an AC magnetic field [68]. The disuccinimidyl suberate (DSS) linked Gd–Tex would thus contribute T1 relaxation, as well as ROS production through radiosensitization. To confirm whether this Gd– Tex magnetic nanoparticle (Gd–Tex MNPs) displayed T1 and T2 relaxation, an MRI phantom study demonstrated both T1 and T2 contrast enhancements, displaying simultaneous T1 bright and T2 dark contrast in images [68,69]. This confirmed the Gd–Tex (T1 active agent) and magnetic nanoparticle (T2 active agent) retained and displayed intrinsic properties in MRI studies. The importance of this is that the majority of commercially available contrast agents, such as Magnevist and Feridex, only possess either T1 or T2 contrast enhancement, and thus Gd–Tex MNPs may offer a new dual-modal T1/T2 contrast agent for clinical applications [45]. The therapeutic properties of Gd–Tex MNPs were also evaluated for its capability to produce ROS and elicit hyperthermia through effective heat-generation of the MNP core. Using an MDA-MB231 breast cancer cell line, the authors demonstrated Gd–Tex MNPs ability to act as a radiosensitizer, in vitro and in vivo [45]. Given Gd–Tex capability to produce ROS, it was postulated that this would make cancer cells more vulnerable to apoptotic magnetic hyperthermia, suggesting even lower temperatures would elicit a therapeutic response. To validate this hypothesis MDAMB-231 xenograft mice (tumour size = 100 mm3) were given an intratumoural injection of Gd–Tex MNPs (75 lg) and subjected to hyperthermia conditions [68]. Hyperthermia was achieved by placing mice into a water-cooled magnetic induction coil with an AC

magnetic field (500 kHz at 30 kA m 1) applied to achieve a constant tumour temperature of 43 ± 1 °C for 30 min [68]. After receiving only one treatment and being monitored for 14 consecutive days, the treatment arm receiving hyperthermia treatment with Gd–Tex MNPs showed the absence of tumours after 8 days, compared to a control group receiving unfunctionalized MNPs having a significant amount of tumour remaining after 8 days (V/Vinitial = 0.6) [68]. The significant reduction in tumour burden observed constitutes Gd-MNPs as efficacious low-temperature magnetic hypothermia agents, addressing a challenging field with frequent occurrence of thermal tolerance development. As such, this study was the first of its kind, achieving both low-temperature hyperthermia and high therapeutic efficacy through an efficient and well-designed ‘‘double-effector” nanoparticle system. 5.2. Liposomal delivery vehicles In recent work, texaphyrin has been combined with liposomal nanotechnology for applications in metastatic liver cancer. A lipidbased nanoparticle comprising of polyethylene glycol-cholesterol (PEG-cholesterol), 1,2-dioleoyl-sn-glycero-3-phosphoethanola mine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)-2000] (mPEGDSPE), and 1,2-distear oyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000] (folate-PEG-DSPE) at varying molar ratios was loaded with a Gd–Tex doxorubicin (Dox) prodrug conjugate (via a disulphide bond) in the core [70]. The conjugate was designed to cleave

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Fig. 4. General strategy for liposomal texaphyrin theranostics for metastatic liver cancer. (a) Structures of conjugates with and without diol moieties capable of interacting with GSH found in cancer cells. (b) Proposed schematic illustration of dox release and fluorescence enhancement produce by FL-1 upon exposure to cellular thiols. Reproduced with permission from Ref. [70]. Copyright 2016 ACS Publications.

in the presence of glutathione (GSH), which is found to be upregulated in cancer cells (Fig. 4) [70]. Additionally, the nanosystem acts as a sensor, which is fluorescence sensitive in the presence of GSH. When initially prepared, it produces no significant fluorescence. However, in the presence of GSH, there is an increase in fluorescence intensity at 592 nm, and thus it can be inferred that this event is attributed to the release of free doxorubicin. The nanoparticles were modulated with folate-receptor-targeted moieties to simultaneously improve the solubility and tumour targeting effectiveness. To demonstrate this, these folate-decorated liposomes (termed FL1) were analysed in vitro in KB and CT26 cell lines, which are known to express folate receptors on the cell surface [70]. Fluorescence turn on studies and HPLC analyses demonstrated selective uptake and cleavage, releasing free Dox in these cell lines. In comparison, studies using cell lines that are known to have low expression of folate receptors on the cell surface (HepG2 and NIH3T3) with FL-1 produced markedly lower antiproliferative effects when compared to those observed in the KB and CT26 cell lines [70]. Since these FL-1 liposomes possessed a Gd–Tex core, this known paramagnetic entity enabled in vivo MRI in clinical relevant cancer mouse models. FL-1 enabled MRI showed T1 contrast enhancement in an early stage metastatic liver cancer model (CT26 cell line). FL-1 derived enhanced MR signals were observed in tumour regions as early as 30 min after tail vein injection, where a slow decline in signal intensity over time indicated slow clearance of the conjugate from the tumour site [70]. These results demonstrate a powerful ability of the FL-1 nanoparticle to enable early state metastatic disease diagnosis, which can potential improve treatment effectiveness and subsequent patient outcomes. To this end, it was demonstrated using subcutaneous and metastatic liver cancer mouse models (CT26 derived) that FL-1 (2.5 mg/ kg administered intravenously in four disease) was capable of reducing tumour burden in vivo, using time-dependent tumour regrowth studies [70]. The diagnostic and therapeutic capabilities of the nanosystem developed constitute a new role Gd–Tex that can serve further strengthening the connection between texaphyrins and nanotechnology. 5.3. Texaphyrins as nanoparticle building blocks The aforementioned nanosystems used pre-formed nanoparticles to combine with texaphyrins, in order to elicit a particular

desirable functionality. Typically, there are two different approaches to creating multifunctional nanoparticles. The first approach, an ‘‘all-in-one” strategy, combined multiple buildings blocks to create multifunctional nanoparticles. Contrasting this is an approach where a nanoparticle is composed of intrinsic multifunctional building blocks [71–73]. This simplified approach lowers translation hurdles; however, the discovery and synthesis of inherently multifunctional building blocks, in particular organic based ones, are of significant difficulty. One such report that has combined texaphyrins with this nanoparticle design approach is called ‘‘nanotexaphyrin” [74]. Nanotexaphyrin is composed of a novel self-assembling amphiphilic texaphyrin-phospholipid conjugate, creating an all organic based multifunctional nanoparticle. Nanotexaphyrin exhibits a liposome-like structure, strong absorption of near-infrared photons, high-density packing of macrocyclic monomers, and structure-dependent fluorescence quenching. Thus, this is the first report for the use of texaphyrins as nanoparticle build blocks, separating itself from previous nanoparticle– texaphyrin systems as a class of its own. The authors chose to investigate a paramagnetic Mn–texaphyrin based agent due to its capability to show strong reduction in both T1 and T2 relaxation constants in tissues. One of the striking features of Mn–nanotexaphyrin is the protocol developed to synthesize these nanomaterials. It was demonstrated that Mn– nanotexaphyrin can be prepared through a one-pot synthesis and self-assembly, starting from the novel texaphyrin-phospholipid conjugate. Interestingly, Mn instantaneously chelates to texaphyrin in temperatures as low as 20 °C upon the addition of an organic base (Fig. 5a). Since the reaction is quantitative, no additional purification is required after solvent removal, thus enabling a facile self-assembly process that follows. Mn–nanotexaphyrin is capable of being made entirely of texaphyrin-phospholipid without any excipients. However, the formulation the authors chose to use included 40 molar % cholesterol and 5 molar% 1,2-distear oyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-2KPEG), to improve in vivo pharmacokinetics [75]. The intrinsic solution phase relaxivity properties of Mn–nanotexaphyrin was investigated to elucidate fundamental parameters of these magnetic materials. Solution-based MRI evaluation at high field strength (7 T) showed a calculated r1 (linear regression of a R1[1/T1] vs. contrast agent concentration plot) of 0.81 mM 1 s 1

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Fig. 5. (a) One-pot synthesis and self-assembly of Mn–nanotexaphyrin, with corresponding absorption and mass spectra of texaphyrin-phospholipid, and dynamic light scattering size and transmission electron microscopy (TEM) of Mn–nanotexaphyrin. Key: (1) texaphyrin-lipid, Mn(OAc)2 in methanol; (2) Mn–texaphyrin-lipid; (3) lipid film; (4) Mn–nanotexaphyrin; (A) NEt3 at 08 C; (B) DSPE-2KPEG, cholesterol, evaporation; (C) hydrated with PBS, self-assembly. (b) T1- and T2-weighted imaging of the tumour site (top) and lymph node (bottom) of a head and neck VX-2 rabbit tumour, with yellow arrows indicating lymphatic drainage. Reproduced with permission from Ref. [74]. Copyright 2016 John Wiley & Sons, Inc.

and 0.99 mM 1 s 1 for intact and dissociated Mn–nanotexaphyrin, respectively. From this, it can be inferred that there is no structure dependence on T1 effects for Mn–nanotexaphyrin. Analyses of T2 properties showed a calculated r2 (linear regression of a R2[1/T2] vs. contrast agent concentration plot) of 13.59 mM 1 s 1 and 8.20 mM 1 s 1 for intact and dissociated Mn–nanotexaphyrin,

respectively. In this context, it was demonstrated that there is a significant structural dependence on T2 relaxation, an effect that is attributed by an increase in the relative saturation magnetization with increasing particle size, a correlation demonstrated in ferrites and iron based nanoparticles [76–78]. Furthering the solution-based analysis, the stability of Mn–nanotexaphyrin was

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J.M. Keca, G. Zheng / Coordination Chemistry Reviews xxx (2017) xxx–xxx

evaluated for both the Mn–texaphyrin chelation and the Mn–nanotexaphyrin structural stability. The stability of Mn-chelation to nanotexaphyrin was 99.5 ± 0.8% and 98.8 ± 0.8% after 24 and 48 h in 50% FBS, respectively, indicating a complex exhibiting strong thermodynamic and kinetic stability. The resilience to Mndissociation can be attributed to Mn-coordination causing the sp3-texaphyrin to become fully aromatic when chelating a metal ion, the thermodynamic favourability of aromaticity may prevent Mn-dissociation. To investigate the structural stability of Mn–nanotexaphyrin, the unique structure dependent r2 properties were taken advantage of to utilize T2-weighted imaging, where structural degradation can be inferred upon decreases in R2 values. Mn–nanotexaphyrin in 50% FBS was shown to possess structural stability for up to 48 h, with no significant decrease in R2. Mn–nanotexaphyrin was then evaluated in vivo in a VX-2 head and neck tumour bearing rabbit with cervical lymph node metastases. Assessing its capability for contrast enhancement in a lymphoscintigraphy procedure, Mn–nanotexaphyrin was subcutaneously injected in a site proximal to the tumour, with T1- and T2-weighted imaging 2 h after aimed to enhance the visualization of lymphatic draining from the tumour site to metastatic disease lymph nodes. Imaging results showed strong increased visualization of lymphatic drainage from the tumour site to the adjacent metastatic lymph node (Fig. 5b). Proof-of-concept work suggests that Mn–nanotexaphyrin may possess a role as an MRI contrast agent for sentinel lymph nodes (SLNs) biopsy procedures. Given the majority of systemic toxicity of MRI contrast agents lies upon the dissociation of the metal cation from the macrocyclic chelator, the strong kinetic and thermodynamic stability of the Mn–nanotexaphyrin coordination suggested this stability can translate to in vivo safety. To demonstrate this, a high dose of Mn–nanotexaphyrin (10 mg
kg 1) was injected into healthy female BALB/c mice (n = 5) to evaluate potential acute toxicity effects. Blood tests and histopathology analyses of liver, kidney, heart, muscle, adrenal, lung, spleen, and large intestine substantiate that Mn–nanotexaphyrin does not exhibit acute toxicity effects 24 h post injection. To combine the versatility of the nanotexaphyrin technology with the chelation prowess of texaphyrins, a library of 17 additional metal–texaphyrin-phospholipid conjugates was synthesized. The vast capability of texaphyrins, such as radiotherapy, radiosensitization, PET and SPECT imaging, MRI, photodynamic therapy, and fluorescence imaging, is now capable in a nanomaterial, metallo-nanotexaphyrins. The importance of nanotexaphyrin cannot be understated, as this technology has the capacity to catapult texaphyrins back to the forefront of novel research endeavours. Nanotexaphyrin effectively combines the power of nanotechnology, with that of texaphyrins chelation and dynamic application properties, creating a new nanosystem capable of a variety of applications.

6. Conclusions Texaphyrins are macrocycles with unrivaled coordinative limits, possessing a range of metal complexes that include many medically relevant metal cations. Their unique physical and photonic properties have led to a vast amount of research efforts that ultimately lead to clinical evaluations of metallotexaphyrins. The combination of texaphyrin and nanotechnology aims to solve the shortcomings of individual metallotexaphyrin molecules, with promising research emerging over recent years. Particularly important is nanotexaphyrins, a combination of texaphyrins with nanoparticles that are in their infancy of investigations. The aim of this review was to illustrate the remarkable history and trajectory of a compound we believe has significant potential that has

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