Photodynamic therapy (PDT) is a clinically-approved medical modality to treat different types of localised conditions such as cancer, infections or skin conditions. Pancreatic cancer (PC) is a deadly cancer displaying a dramatic overall prognosis that has barely improved in decades as the majority of PC patients are diagnosed at a locally advanced or metastatic stage and cannot benefit of surgical resection which is the only curative treatment, the overall 5-year survival rate remains extremely low. Thus, finding new therapies for non-metastatic PC to improve local control as a bridge to surgical resection and improve survival outcomes remains a huge challenge. In this context, PDT could be an interesting option. This review will focus on the use of PDT with targeted photosensitisers or nanoparticles to treat PC in recent studies (2020-2025) from in vitro to in vivo experiments and clinical applications.

Chlorins are among the most interesting photosensitizers for photodynamic therapy because they exhibit a high quantum yield of the singlet oxygen generation and absorbance in the deep red. Indeed the penetration depth of light into skin increases with wavelength from the UV to the near-infrared light range. Even if chlorins can be synthesized, they are present in the nature and the most abundant natural chlorin is the chlorophyll. After acetone extraction of chlorophyll a from spirulina maxima, it is possible to synthesize a derivative, the purpurin 18, which has an absorbance around 700 nm (CHCl3) thanks to an additional anhydride exocyclic ring compared to the chlorin p6, whose maximum absorbance wavelength is at 660 nm (CHCl3). The disadvantage is that this anhydride exocyclic ring is very reactive and can be easily opened by a nucleophile to lead to a derivative of chlorin p6. To preserve a cycle and thus the absorbance around 700 nm, previous works have shown that it is possible to open purpurin 18 with an amine and to recyclize to lead to purpurin imide derivatives, which have also shown very important phototoxicity. In this work, we have therefore synthesized various derivatives of purpurin imide, bearing different peripherical reactive functional groups such as amino, sulfhydryl, maleimide, azide and alkyne to allow subsequent functionalization and open up the possibilities of using them. The structures of all new derivatives of purpurin imide were characterized by NMR and UV/visible spectroscopy and mass spectrometry.

Starting from purpurin-18, a stable purpurin-18 imide derivative with intensive absorption in the near infrared has been synthesized. The opening of the exocycle anhydride by a primary alkylamine bearing an adamantyl group, allows after cyclization the formation of an imide function. This reaction led to the purpurinimide adamantane derivative (PIA) which enables the inclusion of a photosensitizer in the cavity of cationic cyclodextrin coupled to cellulose nanocrystals (CNCs/β-CD+). Preliminary in vitro results showed that CNCs/β-CD+ complexes improved internalization of photosensitizers into HCT116 and HT-29 colorectal cancer cell lines. Moreover, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay of CNCs/β-CD+/PIA complexes showed significant dose-dependent phototoxicity after illumination with red light, with IC50 values of 2.5 and 8.7 nM, for HT 116 and HT-29, respectively, and very low dark toxicity. The current results suggest that these nanoparticle/photosensitizer complexes are promising and useful tools for photodynamic therapy (PDT).

Photodynamic therapy (PDT) has emerged as a promising and evolving modality in cancer treatment leveraging light-sensitive compounds known as photosensitizers to selectively induce cell death in malignant tissues through the generation of reactive oxygen species (ROS). This review delves into the intricate mechanisms of PDT highlighting the pivotal role of photosensitizers and the resultant oxidative stress that damages cancer cells. It explores the versatile applications of PDT across various cancer types alongside the advantages and limitations inherent to this therapy. Recent technological advancements including improved photosensitizers and novel light delivery systems are also discussed. Additionally the review examines the critical role of arachidonic acid (AA) metabolism in cancer progression detailing the cyclooxygenase, lipoxygenase and cytochrome P450 pathways and their contributions to tumor biology. By elucidating the interplay between PDT and AA metabolism the review underscores the potential of targeting AA metabolic pathways to enhance PDT efficacy. Finally it provides clinical and translational perspectives highlighting ongoing research and future directions aimed at optimizing PDT for improved cancer treatment outcomes.

Curcumin, a bioactive compound derived from the rhizome of Curcuma longa L., has garnered significant attention for its potent anticancer properties. Despite its promising therapeutic potential, its poor bioavailability, rapid metabolism, and low water solubility hinder curcumin’s clinical application. Nanotechnology offers a viable solution to these challenges by enabling the development of curcumin-based nanoparticles (CNPs) that enhance its bioavailability and therapeutic efficacy. This review provides a comprehensive overview of the recent advancements in the design and synthesis of CNPs for cancer therapy. We discuss various NP formulations, including polymeric, lipid-based, and inorganic nanoparticles, highlighting their role in improving curcumin’s pharmacokinetic and pharmacodynamic profiles. The mechanisms by which CNPs exert anticancer effects, such as inducing apoptosis, inhibiting cell proliferation, and modulating signaling pathways, are explored in details. Furthermore, we examine the preclinical and clinical studies that have demonstrated the efficacy of CNPs in treating different types of tumors, including breast, colorectal, and pancreatic cancers. Finally, the review addresses the current challenges and future perspectives in the clinical translation of CNPs, emphasizing the need for further research to optimize their design for targeted delivery and to enhance their therapeutic outcomes. By synthesizing the latest research, this review underscores the potential of CNPs as a promising avenue for advancing cancer therapy.

Antimicrobial photodynamic therapy (aPDT) is a promising strategy to overcome issues related to antibiotic resistance. Here the rationale for designing new photosensitizers is described based on the functionalization of bodipy dyes with triarylphosphonium rotaxanes, and an in-depth characterization of their photophysical properties, applying different spectroscopic techniques, including ultrafast transient absorption spectroscopy is provided. While the addition of halogen atoms to some of the structures provides them the ability to efficiently produce singlet oxygen in organic solvents, such property is suppressed in water, where all the investigated compounds aggregate into spherical nanoparticles. The latter, independently of the presence of bromine, demonstrate high photothermal conversion efficiency and have been tested as photosensitizers in antibacterial photothermal therapy, highlighting the potential of self-assembled organic nanostructures based on bodipy dyes for developing new and versatile nanomaterials for photomedicine applications.

Bisacridinyl-bisarginyl porphyrin (BABAP) is a trisintercalating derivative of a tricationic porphyrin, formerly designed and synthesized in order to selectively target and photosensitize the ten-base pair palindromic sequence d(CGGGCGCCCG)(2). We resorted to the previously derived (Far et al., 2004) lowest energy-minimized (EM) structure of the BABAP complex with this sequence as a starting point. We performed polarizable molecular dynamics (MD) on this complex. It showed, over a 150 ns duration, the persistent binding of the Arg side-chain on each BABAP arm to the two G bases upstream from the central porphyrin intercalation site. We subsequently performed progressive shortenings of the connector chain linking the Arg-Gly backbone to the acridine, from n=6 methylenes to 4, followed by removal of the Gly backbone and further connector shortenings, from n=4 to n=1. These resulted into progressive deformations ('kinks') of the DNA backbone. In its most accented kinked structure, the DNA backbone was found to have a close overlap with that of DNA bound to Cre recombinase, with, at the level of one acridine intercalation site, negative roll and positive tilt values consistent with those experimentally found for this DNA at its own kinked dinucleotide sequence. Thus, in addition to their photosensitizing properties, some BABAP derivatives could induce sequence-selective, controlled DNA deformations, which are targets for cleavage by endonucleases or for repair enzymes.

Photodynamic therapy (PDT) is a clinically approved, non-invasive therapy currently used for several solid tumors, triggering cell death through the generation of reactive oxygen species (ROS). However, the hydrophobic nature of most of the photosensitizers used, such as chlorins, limits the overall effectiveness of PDT. To address this limitation, the use of nanocarriers seems to be a powerful approach. From this perspective, we have recently developed water-soluble and biocompatible, fluorescent, organic nanoparticles (FONPs) functionalized with purpurin-18 and its derivative, chlorin p6 (Cp6), as new PDT agents. In this study, we aimed to investigate the induced cell death mechanism mediated by these functionalized nanoparticles after PDT photoactivation. Our results show strong phototoxic effects of the FONPs[Cp6], mediated by intracellular ROS generation, and subcellular localization in HCT116 and HT-29 human colorectal cancer (CRC) cells. Additionally, we proved that, post-PDT, the FONPs[Cp6] induce apoptosis via the intrinsic mitochondrial pathway, as shown by the significant upregulation of the Bax/Bcl-2 ratio, the activation of caspases 9, 3, and 7, leading poly-ADP-ribose polymerase (PARP-1) cleavage, and DNA fragmentation. Our work demonstrates the photodynamic activity of these nanoparticles, making them promising candidates for the PDT treatment of CRC.

Photochemically CO-releasing molecules (photoCORMs) have recently raised high hopes in the fight against antibiotic-resistant bacteria, but the underlying mechanisms are still badly known. It has been hypothesized that, in addition to a direct biochemical activity of the photoCORMs, the generation of both carbon monoxide (CO) and singlet oxygen (1O2) plays a key role in the phototherapeutic efficiency. To clarify this point, nanomaterials that produce only CO, only 1O2, or both, were prepared by associating various photoCORMs with cellulose nanocrystals, which act as biocompatible and hydrophilic carriers. The antibacterial efficiency of these nanomaterials, measured on Staphylococcus aureus and Pseudomonas aeruginosa, was compared. This study is one more step towards the development of original and efficient photoantimicrobials.

A series of phenalenone-lipid conjugates (1A, 1B, 1C, 2) have been synthesized to compensate for the poor water solubility of the photosensitizer phenalenone (PN) and promote the formation of nano-assemblies. We show that the organization and structure of monolayers upon compression strongly depend on the nature of the linker connecting PN to the lipid backbone, and the number of C18 chains. Monolayer properties at the air-water interface were analyzed by surface pressure measurements, Brewster angle and atomic force microscopies, grazing incidence X-ray diffraction, and X-ray reflectivity. Whereas conjugate 1C (ester bond) organizes into multilayers upon compression, conjugates 1A, 1B, and 2 form stable monolayers whose structure is controlled by van der Waals (vdW) interactions between C18 chains, intermolecular H-bonding involving the linker, and for 1B, π-π stacking of PN moieties. Conjugate 1A (amide-triazole linker) is structured into a rectangular network of chains with an order that extends only to the molecule of the adjacent cell. Conjugate 1B (amide bond) forms two incommensurate networks, one for the chains and the other for the headgroups. The distance between molecules in the next near neighbor chain lattice and the sufficient degree of freedom of PN groups allows them to pile up via π-π interactions below the chains in a rectangular cell. Conjugate 2 with its double chain adopts a similar behavior to that of a saturated phospholipid. Strong vdW interactions predominate and allow, at high surface pressure, hexagonal packing with no chain tilt. The distance between molecules prevents PN stacking. The identified PN derivative structures explain the linker’s impact on the formation and stability of nano-assemblies.

Most photosensitizers of interest for photodynamic therapy—especially porphyrinoids and chlorins—are hydrophobic. To circumvent this difficulty, the use of nanocarriers is an attractive strategy. In this perspective, we have developed highly water-soluble and biocompatible fluorescent organic nanoparticles (FONPs) made from citric acid and diethyltriamine which are then activated by ethlynene diamine as nanoplatforms for efficient photosensitizers (PSs). Purpurin 18 (Pp18) was selected as a biosourced chlorin photosensitizer combining the efficient single oxygen generation ability and suitable absorption in the biological spectral window. The simple reaction of activated FONPs with Pp18, which contains a reactive anhydride ring, yielded nanoparticles containing both Pp18 and Cp6 derivatives. These functionalized nanoparticles combine solubility in water, high singlet oxygen generation quantum yield in aqueous media (0.72) and absorption both in the near UV region (FONPS) and in the visible region (Soret band approximately 420 nm as well as Q bands at 500 nm, 560 nm, 660 nm and 710 nm). The functionalized nanoparticles retain the blue fluorescence of FONPs when excited in the near UV region but also show deep-red or NIR fluorescence when excited in the visible absorption bands of the PSs (typically at 520 nm, 660 nm or 710 nm). Moreover, these nanoparticles behave as efficient photosensitizers inducing colorectal cancer cell (HCT116 and HT-29 cell lines) death upon illumination at 650 nm. Half maximal inhibitory concentration (IC50) values down to, respectively, 0.04 and 0.13 nmol/mL were observed showing the potential of FONPs[Cp6] for the PDT treatment of cancer. In conclusion, we have shown that these novel biocompatible nanoparticles, which can be elaborated from biosourced components, both show deep-red emission upon excitation in the red region and are able to produce singlet oxygen with high efficiency in aqueous environments. Moreover, they show high PDT efficiency on colorectal cancer cells upon excitation in the deep red region. As such, these functional organic nanoparticles hold promise both for PDT treatment and theranostics.

In the context of designing innovative anticancer agents, the synthesis of a series of chalcones bearing a 3,4,5-trimethoxylated A ring and a variety of B rings, including phenols and original heterocycles such as chromones, was conducted. For this end, Claisen–Schmidt condensation was performed in basic or acidic conditions between the common starting material 3,4,5-trimethoxyacetophenone and appropriate aldehydes; this allowed the recovery of fifteen chalcones in moderate–good yields. The synthesized compounds were screened for their antiproliferative activity against colorectal and prostatic cancer cells, using a colorimetric MTT assay. Among the new chromonyl series, chalcone 13 demonstrates an interesting antiproliferative effect, with IC50 values in the range of 2.6–5.1 µM at 48 h. Then, our study evidenced that indolyl chalcone 10 exhibits excellent activity towards the selected cell lines (with IC50 less than 50 nM). This compound has already been described and has been shown to be a potent anticancer agent against other cancer cell lines. Our investigations highlighted apoptosis induction, through several pro-apoptotic markers, of these two heterocyclic chalcones. Considering phenolic chalcones, compounds 2 and 8 were found to be the most active against cell proliferation, exerting their effect by inducing the depolymerization of cell microtubules. The most promising compounds in this series will be selected for application in a strategy of vectorization by either active or passive targeting.

Despite advances achieved in the health field over the last decade, infections caused by resistant bacterial strains are an increasingly important societal issue that needs to be addressed. New approaches have already been developed to overcome this problem. Photodynamic antimicrobial chemotherapy (PACT) could provide a promising alternative method to eradicate microbes. This approach has already inspired the development of innovative surfaces. Interesting results were achieved against Gram-positive bacteria, but it also appeared that Gram-negative strains, especially Pseudomonas aeruginosa, were less sensitive to PACT. However, materials coated with cationic porphyrins have already proven their wide-spectrum activity, but these materials were not suitable for industrial-scale production. The main aim of this work was the design of a large-scale evolutionary material based on PACT and antibiotic prophylaxis. Transparent regenerated cellulose has been simply impregnated with a usual cationic porphyrin (N-methylpyridyl) and an antimicrobial peptide (polymyxin B). In addition to its photophysical properties, this film exhibited a wide-spectrum bactericidal activity over 4 days despite daily application of fresh bacterial inoculums. The efficiency of PACT and polymyxin B combination could help to reduce the emergence of bacterial multi-resistant strains and we believe that this kind of material would provide an excellent opportunity to prevent bacterial contamination of bandages or packaging.

Antibiotic-resistant bacteria represent a growing threat to global health and efforts continue to be made to seek new ways of addressing this issue. Photoactivatable carbon monoxide (CO)-releasing molecules (photoCORMs) could be an alternative solution to conventional antibiotics, but their mechanism of action is complex and still badly known. In the present work, a tricarbonylrhenium(I) complex (Re-Phe(TPP)) was developed, as well as a more hydrophobic analogue substituted by an adamantyl moiety (Re-Ada(TPP)). When irradiated in the near UV, these molecules generate rapidly one molecule of CO, as well as small amounts of singlet oxygen (1O2). Their decarbonylated photoproducts D-Re-Phe(TPP) and D-Re-Ada(TPP) generate only 1O2, on a prolonged period of time. Finally, the complexes were immobilized on a biocompatible cellulose nanocrystal (CNC) matrix, so that only the diffusive species (CO and 1O2) may be the active ones. The bactericidal activity of all these systems was evaluated on two bacteria strains, causative of the main wound infections. No compound was active on Pseudomonas aeruginosa. In contrast, free Re-Phe(TPP) appeared to be a very good antibacterial agent in the dark on Staphylococcus aureus. The same molecule adsorbed on the CNC material was ineffective. Consequently, its activity was mainly attributed to direct biological effect. The adamantyl derivative Re-Ada(TPP) was more active in the presence of light, while the decarbonylated photoproduct D-Re-Phe(TPP) showed moderate activity, suggesting that the production of 1O2 is not enough to induce a significant bactericidal effect. This work allows to identify the limits of Re(I) photoCORMs and corresponding nanomaterials, which are still little used in the fight against bacteria, and it provides good indications on how to improve their design.

Acne is one of the most common dermatological conditions, peaking during adolescence and early adulthood, affecting about 85% of individuals aged 12–24. Although often associated with teenage years, acne can occur at any age, impacting over 25% of women and 12% of men in their forties. Treatment strategies vary depending on the severity, including the use of topical gels or creams containing benzoyl peroxide and retinoids, antibiotics, and systemic or topical isotretinoin. However, these treatments can cause irritation, allergies, and other toxic side effects. Currently, there is no natural-based alternative for antibacterial photodynamic therapy targeting acne using marine drugs or extracts. Through a bioguided screening approach, we identified the ethanol extract of Skeletonema marinoi as highly phototoxic against three bacterial species associated with acne—Cutibacterium acnes, Staphylococcus aureus, and Staphylococcus epidermidis. This extract exhibited phototoxicity in planktonic bacteria under white and red light, disrupted bacterial biofilms, reduced sebum production but also showed phototoxicity in keratinocytes, highlighting the importance of the specific targeting of treatment areas. Further investigations, including fractionation and high-resolution structural analysis, linked the observed phototoxicity to a high concentration of pheophorbide a in the extract. Given its notable in vitro efficacy, this extract holds promising potential for clinical evaluation to manage mild acne. This discovery paves the way for further exploration of Skeletonema pigment extracts, extending their potential applications beyond acne phototherapy to include dermocosmetics, veterinary medicine, and other phototherapy uses.

Multiplex Coherent Anti-Stokes Raman Scattering (M-CARS) is an innovative nonlinear spectroscopic approach designed to characterize the vibrational modes of molecular structures. Coherent Raman scattering has been used for the characterization of biomedical targets for about 20 years and the multiplex aspect was introduced 10 years ago thanks to the use of a supercontinuum laser system. For each of these systems, the combination of a pump and a probe wave, driven by an external delay line, is however required to produce the vibrations. In the present work, we propose a new M-CARS system, free of the external delay line. A few-mode microstructured fiber enables merging both wave-packets (pump and supercontinuum) within a single waveguide. We showcase the capability of this system in generating hyperspectral images of biochemically active compounds. Curcumin I, the principal yellow compound isolated from Curcuma longa (Turmeric), is distinguishable by its multiple functional groups that display a nonlinear spectroscopic behavior.

Curcumin has been shown to exert beneficial effects in peripheral neuropathies. Despite its known biological activities, curcumin has unfavorable pharmacokinetics. Its instability has been linked to its failure in clinical trials of curcumin for the treatment of human pathologies. For this reason, we developed curcumin-loaded cyclodextrin/cellulose nanocrystals (NanoCur) to improve its pharmacokinetics. The present study aims to assess the potency of a low dose of NanoCur in 2 Charcot-Marie-Tooth disease type 1A (CMT1A) rodent models at different stages of the disease. The efficiency of NanoCur is also compared to that of Theracurmin (Thera), a commercially available curcumin formulation. The toxicity of a short-term and chronic exposure to the treatment is investigated both in vitro and in vivo, respectively. Furthermore, the entry route, the mechanism of action and the effect on the nerve phenotype are dissected in this study. Overall, the data support an improvement in sensorimotor functions, associated with amelioration in peripheral myelination in NanoCur-treated animals; an effect that was not evident in the Thera-treated group. That was combined with a high margin of safety both in vivo and in vitro. Furthermore, NanoCur appears to inhibit inflammatory pathways that normally include macrophage recruitment to the diseased nerve. This study shows that NanoCur shows therapeutic benefits with minimal systemic toxicity, suggesting that it is a potential therapeutic candidate for CMT1A and, possibly, for other neuropathies.

Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer.