Hypoxia presents a two-fold challenge in the treatment of cancer, as low oxygen conditions induce biological changes that make malignant tissues simultaneously more aggressive and less susceptible to standard chemotherapy....
Ru(II)
complexes that undergo photosubstitution reactions from
triplet metal-centered (3MC) excited states are of interest
in photochemotherapy (PCT) due to their potential to produce cytotoxic
effects in hypoxia. Dual-action systems that incorporate this stoichiometric
mode to complement the oxygen-dependent photosensitization pathways
that define photodynamic therapy (PDT) are poised to maintain antitumor
activity regardless of the oxygenation status. Herein, we examine
the way in which these two pathways influence photocytotoxicity in
normoxia and in hypoxia using the [Ru(dmp)2(IP-nT)]2+ series (where dmp = 2,9-dimethyl-1,10-phenanthroline
and IP-nT = imidazo[4,5-f][1,10]phenanthroline
tethered to n = 0–4 thiophene rings) to switch
the dominant excited state from the metal-based 3MC state
in the case of Ru-phen–Ru-1T to the
ligand-based 3ILCT state for Ru-3T and Ru-4T. Ru-phen–Ru-1T, having
dominant 3MC states and the largest photosubstitution quantum
yields, are inactive in both normoxia and hypoxia. Ru-3T and Ru-4T, with dominant 3IL/3ILCT states and long triplet lifetimes (τTA = 20–25
μs), have the poorest photosubstitution quantum yields, yet
are extremely active. In the best instances, Ru-4T exhibit
attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar
in hypoxia, with phototherapeutic index values in normoxia of 105–1012 and 103–106 in hypoxia. While maximizing excited-state deactivation through
photodissociative 3MC states did not result in bonafide
dual-action PDT/PCT agents, the study has produced the most potent
photosensitizer we know of to date. The extraordinary photosensitizing
capacity of Ru-3T and Ru-4T may stem from
a combination of very efficient 1O2 production
and possibly complementary type I pathways via 3ILCT excited
states.
Hypoxia presents a challenge to anticancer
therapy, reducing the
efficacy of many available treatments. Photodynamic therapy is particularly
susceptible to hypoxia, given that its mechanism relies on oxygen.
Herein, we introduce two new osmium-based polypyridyl photosensitizers
that are active in hypoxia. The lead compounds emerged from a systematic
study of two Os(II) polypyridyl families derived from 2,2′-bipyridine
(bpy) or 4,4′-dimethyl-2,2′-bipyridine (dmb) as coligands
combined with imidazo[4,5-f][1,10]phenanthroline
ligands tethered to n = 0–4 thiophenes (IP-nT). The compounds were characterized and investigated for
their spectroscopic and (photo)biological activities. The two hypoxia-active
Os(II) photosensitizers had n = 4 thiophenes, with
the bpy analogue 1-4T being the most potent. In normoxia, 1-4T had low nanomolar activity (half-maximal effective concentration
(EC50) = 1–13 nM) with phototherapeutic indices
(PI) ranging from 5500 to 55 000 with red and visible light,
respectively. A sub-micromolar potency was maintained even in hypoxia
(1% O2), with light EC50 and PI values of 732–812
nM and 68–76, respectively currently among the largest
PIs for hypoxic photoactivity. This high degree of activity coincided
with a low-energy, long-lived (0.98–3.6 μs) mixed-character
intraligand charge-transfer (3ILCT)/ligand-to-ligand charge-transfer
(3LLCT) state only accessible in quaterthiophene complexes 1-4T and 2-4T. The coligand identity strongly
influenced the photophysical and photobiological results in this study,
whereby the bpy coligand led to longer lifetimes (3.6 μs) and
more potent photo-cytotoxicity relative to those of dmb. The unactivated
compounds were relatively nontoxic both in vitro and in vivo. The
maximum tolerated dose for 1-4T and 2-4T in mice was greater than or equal to 200 mg kg–1, an excellent starting point for future in vivo validation.
Tumor hypoxia renders treatments
ineffective that are directly
(e.g., radiotherapy and photodynamic therapy) or indirectly (e.g.,
chemotherapy) dependent on tumor oxygenation. This study introduces
a ruthenium compound as a light-responsive anticancer agent that is
water-soluble, has minimal dark cytotoxicity, is active at concentrations
as low as 170 pM in ∼18.5% O2 normoxia and near
10 nM in 1% O2 hypoxia, and exhibits phototherapeutic indices
as large as >500,000 in normoxia and >5,800 in 1% O2 hypoxia
using broadband visible and monochromatic blue light treatments. These
are the largest values reported to date for any compound class. We
highlight the response in four different cell lines to improve rigor
and reproducibility in the identification of promising clinical candidates.
Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune...
A zinc-carnosine (ZnCar) metal−organic coordination polymer was fabricated in biologically relevant N-(2hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES) buffer for use as a vaccine platform. In vitro, ZnCar exhibited significantly less cytotoxicity than a well-established zeolitic imidazolate framework (ZIF-8). Adsorption of CpG on the ZnCar surface resulted in enhanced innate immune activation compared to soluble CpG. The model antigen ovalbumin (OVA) was encapsulated in ZnCar and exhibited acid-sensitive release in vitro. When injected intramuscularly on days 0 and 21 in C57BL/6 mice, OVA-specific serum total IgG and IgG1 were significantly greater in all groups with ZnCar and antigen compared to soluble controls. Th1-skewed IgG2c antibodies were significantly greater in OVA and CpG groups delivered with ZnCar for all time points, regardless of whether the antigen and adjuvant were co-formulated in one material or co-delivered in separate materials. When broadly acting Computationally Optimized Broadly Reactive Antigen (COBRA) P1 influenza hemagglutinin (HA) was ligated to ZnCar via its His-tag, significantly greater antibody levels were observed at all time points compared to soluble antigen and CpG. ZnCar-formulated antigen elicited increased peptide presentation to B3Z T cells in vitro and production of IL-2 after ex vivo antigen recall of splenocytes isolated from vaccinated mice. Overall, this work displays the formation of a zinc-carnosine metal−organic coordination polymer that can be applied as a platform for recombinant protein-based vaccines.
In an earlier study of π‐expansive ruthenium complexes for photodynamic and photochemo‐therapies, it was shown that a pair of structural isomers differing only in the connection point of a naphthalene residue exhibited vastly different biological activity. These isomers are further explored in this paper through the activity of their functionalized derivatives. In normoxia, the inactive 2‐NIP isomer (5) can be made as photocytotoxic as the active 1‐NIP isomer (1) by functionalizing with methyl or methoxy groups, while methoxy variants of the 1‐NIP isomer became inactive. In all cases, the singlet oxygen sensitization quantum yield was below 1%. Hypoxic photocytotoxicity was attenuated, with only three of the series showing any activity, notwithstanding the photodissociative ligands. The results here are consistent with the earlier findings in that seemingly minor structural modifications on the non‐strained ligand can dramatically modulate the normoxic and hypoxic activity of these strained compounds and that these changes appear to exert a greater influence on photocytotoxicity than singlet oxygen sensitization or rates of photosubstitution in cell‐free conditions would suggest.
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