Many photoresponsive dyes have been utilized as imaging and photodynamic/photothermal therapy agents. Indocyanine green (ICG) is the only near-infrared region (NIR) organic dye for clinical applications approved by the United States Food and Drug Administration; however, the clinical application of ICG is limited by its poor aqueous solubility, low cancer specificity, and low sensitivity in cancer theranostics. To overcome these issues, a multifunctional nanoplatform based on hyaluronic acid (HA) and ICG-engineered metal-organic framework MIL-100(Fe) nanoparticles (MOF@HA@ICG NPs) was successfully developed for imaging-guided, anticancer photothermal therapy (PTT). The synthesized NPs showed a high loading content of ICG (40%), strong NIR absorbance, and photostability. The in vitro and in vivo imaging showed that the MOF@HA@ICG NPs exhibited greater cellular uptake in CD44-positive MCF-7 cells and enhanced tumor accumulation in xenograft tumors due to their targeting capability, compared to MOF@ICG NPs (non-HA-targeted) and free ICG. The in vitro photothermal toxicity and in vivo PTT treatments demonstrated that MOF@HA@ICG NPs could effectively inhibit the growth of MCF-7 cells/xenograft tumors. These results suggest that MOF@HA@ICG NPs could be served as a new promising theranostic nanoplatform for improved anticancer PTT through cancer-specific and image-guided drug delivery.

5-thyminyl-5,6-dihydrothymine (commonly called spore photoproduct or SP) is the exclusive DNA photo-damage product in bacterial endospores. It is generated in the bacterial sporulation phase and repaired by a radical SAM enzyme, spore photoproduct lyase (SPL), at the early germination phase. SPL utilizes a special [4Fe-4S] cluster to reductively cleave S-adenosylmethionine (SAM) to generate a reactive 5′-dA radical. The 5′-dA radical is proposed to abstract one of the two H atoms at the C6 carbon of SP to initiate the repair process. Via organic synthesis and DNA photochemistry, we selectively labeled the 6-HproS or 6-HproR position with a deuterium in a dinucleotide SP TpT substrate. Monitoring the deuterium migration in enzyme catalysis (employing Bacillus subtilis SPL) revealed that it is the 6-HproR atom of SP that is abstracted by the 5′-dA radical. Surprisingly, the abstracted deuterium was not returned to the resulting TpT after enzymatic catalysis, an H atom from the aqueous buffer was incorporated into TpT instead. This result questions the currently hypothesized SPL mechanism which excludes the involvement of protein residue(s) in SPL reaction, suggesting that some protein residue(s), which is capable of exchanging a proton with the aqueous buffer, is involved in the enzyme catalysis. Moreover, evidence has been obtained for a possible SAM regeneration after each catalytic cycle; however, such a regeneration process is more complex than currently thought, with one or even more protein residues involved as well. These observations have enabled us to propose a modified reaction mechanism for this intriguing DNA repair enzyme.

Planar Möbius aromatic metallacycles show NIR absorption spectrum and the highest carbon coordination number for a metal atom.

5-thyminyl-5,6-dihydrothymine (also called spore photoproduct or SP) is the exclusive DNA photo-damage product in bacterial endospores. It is repaired by a radical SAM (S-adenosylmethionine) enzyme, the spore photoproduct lyase (SPL), at the bacterial early germination phase. Our previous studies proved that SPL utilizes the 5′-dA• generated by SAM cleavage reaction to abstract the H6proR atom to initiate the SP repair process. The resulting thymine allylic radical was suggested to take an H atom from an unknown protein source, most likely the cysteine 141. Here we show that C141 can be readily alkylated in the native SPL by iodoacetamide treatment, suggesting that it is accessible to the TpT radical. SP repair by the SPL C141A mutant yields TpTSO2− and TpT simultaneously from the very beginning of the reaction; no lag phase is observed for the TpTSO2− formation. Should any other protein residue serve as the H donor, its presence would result in TpT as the major product at least for the first enzyme turnover. These observations provide strong evidence to support C141 as the direct H atom donor. Moreover, due to the lack of this intrinsic H donor, the C141A mutant produces TpT via an unprecedented thymine cation radical reduction (proton coupled electron transfer) process, contrasting to the H atom transfer mechanism in the WT SPL reaction. The C141A mutant repairs SP at a rate which is ~3-fold slower than the WT enzyme. Formation of TpTSO2− and TpT exhibit a Vmax deuterium kinetic isotope effect (KIE) of 1.7 ± 0.2 respectively, which is smaller than the DVmax KIE of 2.8 ± 0.3 determined in the WT SPL reaction. These findings suggest that removing the intrinsic H atom donor disturbs the rate-limiting process in the enzyme catalysis. As expected, the pre-reduced C141A mutant only supports ~ 0.4 turnover, which is in sharp contrast to the > 5 turnovers exhibited by the WT SPL reaction, suggesting that the enzyme catalytic cycle (SAM regeneration) is disrupted by this single mutation.

Doing some damage: Spore photoproduct (SP) is the major DNA photodamage product in bacterial endospores. NMR spectroscopic studies of deuterium‐labeled TpT dinucleotides have revealed details of the mechanism for SP formation (see scheme). Upon UV irradiation of [D3]TpT (with a 3′‐T CD3 group), a deuterium atom was transferred exclusively to the 6‐Hpro‐S position. The migrated atom was a hydrogen atom when [D4]TpT with a 3′‐T CH3 group was used.

We present the synthesis and application of a new type of dual magnetic and plasmonic nanostructures for magnetic-field-guided drug delivery and combined photothermal and photodynamic cancer therapy. Near-infrared-absorbing gold nanopopcorns containing a self-assembled iron oxide cluster core were prepared via a seed-mediated growth method. The hybrid nanostructures are superparamagnetic and show great photothermal conversion efficiency (η=61%) under near-infrared irradiation. Compact and stable nanocomplexes for photothermal-photodynamic therapy were formed by coating the nanoparticles with near-infrared-absorbing photosensitizer silicon 2,3-naphthalocyannie dihydroxide and stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. The nanocomplex showed enhanced release and cellular uptake of the photosensitizer with the use of a gradient magnetic field. In vitro studies using two different cell lines showed that the dual mode photothermal and photodynamic therapy with the assistance of magnetic-field-guided drug delivery dramatically improved the therapeutic efficacy of cancer cells as compared to the combination treatment without using a magnetic field and the two treatments alone. The "three-in-one" nanocomplex has the potential to carry therapeutic agents deep into a tumor through magnetic manipulation and to completely eradicate tumors by subsequent photothermal and photodynamic therapies without systemic toxicity.

Spore photoproduct lyase (SPL) repairs a covalent UV-induced thymine dimer, spore photoproduct (SP), in germinating endospores and is responsible for endospores’ strong UV resistance. SPL is a radical SAM enzyme, which uses a [4Fe-4S]1+ cluster to reduce the S-adenosyl-L-methionine (SAM), generating a catalytic 5′-deoxyadenosyl radical (5′-dA•). This in turn abstracts an H atom from SP, generating an SP radical that undergoes β scission to form a repaired 5′-thymine and a 3′-thymine allylic radical. Recent biochemical and structural data suggest that a conserved cysteine donates an H atom to the thymine radical, resulting in a putative thiyl radical. Here we present structural and biochemical data which suggest that two conserved tyrosines are also critical in enzyme catalysis. One (Y99(Bs) in Bacillus subtilis SPL) is downstream of the cysteine, suggesting that SPL uses a novel hydrogen atom transfer (HAT) pathway with a pair of cysteine-tyrosine residues to regenerate SAM. The other tyrosine (Y97(Bs)) has a structural role to facilitate SAM binding; it may also contribute to the SAM regeneration process by interacting with the putative •Y99(Bs) and/or 5′-dA• intermediates to lower the energy barrier for the second H-abstraction step. Our results indicate that SPL is the first member of the radical SAM superfamily (comprising more than 44,000 members) to bear a catalytically operating HAT chain.

We report a facile strategy for engineering diverse particles based on the supramolecular assembly of natural polyphenols and a self-polymerizable aromatic dithiol. In aqueous conditions, uniform and size-tunable supramolecular particles are assembled through π–π interactions as mediated by polyphenols. Owing to the high binding affinity of phenolic motifs present at the surface, these particles allow for the subsequent deposition of various materials (i.e., organic, inorganic, and hybrid components), producing a variety of monodisperse functional particles. Moreover, the solvent-dependent disassembly of the supramolecular networks enables their removal, generating a wide range of corresponding hollow structures including capsules and yolk–shell structures. The versatility of these supramolecular networks, combined with their negligible cytotoxicity provides a pathway for the rational design of a range of particle systems (including core–shell, hollow, and yolk–shell) with potential in biomedical and environmental applications.