Influence of simulated food and oral processing on carotenoid and chlorophyll in vitro bioaccessibility among six spinach genotypes.

Increasing the density of micronutrients and phytochemicals in vegetable foods through plant breeding and processing is of value for consumers. However, the extent to which interactions between genetics and processing (G × P) can be leveraged for green leafy vegetables to improve the delivery of such compounds is unknown. Using spinach as a model, a three-phase in vitro digestion method with and without simulated oral processing (mastication) and coupling to a Caco-2 human intestinal cell culture model was used to determine whether bioaccessibility and intestinal uptake of carotenoids and chlorophylls can be modified from six spinach genotypes, fresh or processed as blanched, sterilized, and juiced products. Carotenoid and chlorophyll bioaccessibility varied significantly with the genotype (p < 0.001) and processing treatment (p < 0.001), with processing having a more profound influence on the bioaccessibility, decreasing micellarization of phytochemicals from juiced (25.8-29.3%), to fresh (19.5-27.9%), to blanched (14.9-20.5%), and sterilized spinach (10.4-13.0%). Oral mastication had a significant influence on the carotenoid bioaccessible content of sterilized spinach (0.3-0.5 µmoles per g DW) as compared to fresh spinach (0.1-0.3 µmoles per g DW), most likely due to the additive effect of thermal processing and mastication on facilitating digestive breakdown of the spinach matrix. Caco-2 accumulation of carotenoid and chlorophyll was modestly but significantly (<0.001) lower in fresh spinach (2.4%) compared to other treatment samples (3.7-4.8%). These results suggest that the genotype, processing treatment, and genotype × processing (G × P) interaction may affect carotenoid and chlorophyll bioaccessibility in spinach and that food processing remains a dominant factor in modulating the bioavailability of these phytochemicals.

Optimized Combination of Photodynamic Therapy and Chemotherapy Using Gelatin Nanoparticles Containing Tirapazamine and Pheophorbide a.

In combination therapy, synergetic effects of drugs and their efficient delivery are essential. Herein, we screened 12 anticancer drugs for combination with photodynamic therapy (PDT) using pheophorbide a (Pba). On the basis of combination index (CI) values in cell viability tests, we selected tirapazamine (TPZ) and developed self-assembled gelatin nanoparticles (NPs) containing both Pba and TPZ. The resulting TPZ-Pba-NPs showed a synergetic effect to kill tumor cells because TPZ was activated under the hypoxic conditions that originated from the PDT with Pba and laser irradiation. After they were injected into tumor-bearing mice via the tail vein, TPZ-Pba-NPs showed 3.17-fold higher blood concentration and 4.12-fold higher accumulation in tumor tissue 3 and 24 h postinjection, respectively. Upon laser irradiation to tumor tissue, TPZ-Pba-NPs successfully suppressed tumor growth by efficient drug delivery and synergetic effects in vivo. These overall results suggest that in vitro screening of drugs based on CI values, mechanism studies in hypoxia, and real-time in vivo imaging are promising strategies in developing NPs for optimized combination therapy.

The Metabolism and Potential Bioactivity of Chlorophyll and Metallo-chlorophyll Derivatives in the Gastrointestinal Tract.

Chlorophyll is the vivid chromophore which imparts the green color to plant leaves, and is consumed by humans through green vegetables. The basic porphyrin structure of chlorophyll binds magnesium in plants, but can bind different divalent metals (e.g., copper, zinc, iron) facilitated by food processing techniques and/or chemical synthesis. This review covers the known elements of chlorophyll and metallo-chlorophyll absorption, distribution, metabolism, excretion in vitro and in vivo. The review discusses what is understood about the ability of these novel metallo-chlorophyll derivatives to deliver essential metals. This review also detail chlorophyll and metallo-chlorophyll toxin binding properties which largely occur during digestion, focusing on toxins including dioxins, heterocyclic aromatic amines, polyaromatic hydrocarbons, and aflatoxin. Finally, the article highlights the gaps in the understanding of the metabolism and metal and toxin-binding bioactivity of this family of molecules.

Bioaccessibility and cellular uptake by Caco-2 cells of carotenoids and chlorophylls from orange peels: A comparison between conventional and ionic liquid mediated extractions.

Native extracts from orange peels were obtained by a conventional method using acetone and, an alternative method using ionic liquid (1-butyl-3-methylimidazolium chloride ([C4mim]Cl)). The bioaccessibilities and cellular uptakes of carotenoids, esters and chlorophylls were evaluated, since the influence of esterification on bioaccessibility and bioavailability is not well established. For this, the extracts were emulsified, submitted to in vitro simulated digestion model according to the INFOGEST protocol, followed by uptake by Caco-2 cells. Compounds were separated, identified and quantified by HPLC-PDA-MS/MS. After digestion, 22.0% and 26.2% of the total carotenoids and 45.9% and 68.7% of the chlorophylls were bioaccessible from the acetone and [C4mim]Cl extracts, respectively. The bioaccessibilities of xanthophylls and carotenes were significantly higher than those of the mono- and diesters. The uptake by Caco-2 cells varied from 130.2 to 131.9 ng/mg cell protein for total carotenoids and from 243.8 to 234.2 ng/mg cell protein for chlorophylls in the acetone and [C4mim]Cl extracts, respectively. In general, xanthophylls and esters were better absorbed than carotenes.

Update on the bioavailability and chemopreventative mechanisms of dietary chlorophyll derivatives.

Chlorophyll, a phytochemical responsible for the green pigmentation in plants, has been studied for almost 100 years for its biological activities in humans. Over the past 30 years, the potential chemopreventative activities of both natural chlorophylls and their processed induced derivatives as well as the semisynthetic forms, such as sodium copper chlorophyllin, have been the focus of many research efforts. Established as potential chemopreventative agents with little to no bioavailability themselves, the activities of chlorophyll derivatives were generally ascribed to their ability to modulate mutagen/carcinogen bioavailability, their metabolism, and ultimately their ability to decrease the "exposure" to these carcinogens for humans at risk. More recently, systemic activities of chlorophyll derivatives have been reported to include modulation of oxidative stress and regulation of xenobiotic metabolizing systems and gene expression of systems critical to prevention of initiation and/or progression of cancer including NFE2-related factor 2, nuclear factor kappa B, TGF-ß, and ß-catenin pathways. With this in mind, the goals of this review are to provide an update to the comprehensive review of Ferruzzi and Blakeslee (2007) to include new insights into the behavior of chlorophyll derivatives in the gut as well as evidence of the systemic bioavailability of chlorophyll derivatives and their metabolites in support of potential impacts in prevention of cancer throughout the body.

Population pharmacokinetic modeling and simulation of HPPH in Chinese patients with esophageal carcinoma.

1. 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, has been widely employed in photodynamic therapy (PDT) for the treatment of malignant lesions. The objective of this study was to characterize the pharmacokinetics of HPPH in Chinese patients using a population pharmacokinetic (PopPK) approach.2. For the first time, a PopPK model of HPPH for Chinese (n = 20) was developed (registration number: CTR20160425). The pharmacokinetics of HPPH was described by a three-compartment model with linear elimination. Through the stepwise addition (p < 0.05) and backward elimination (p < 0.001) approach, fat-free mass (FFM) was identified to be the most significant covariate and V1 increased with FFM. Visual predictive check (VPC) was employed for the evaluation of the final model. Subsequent full covariate analysis indicated that FFM has considerable impact (∼30%) on HPPH exposure and fat mass also has a modest (∼25%) impact.3. The simulations suggested that a dose adjustment of HPPH may be necessary for Chinese and the dose of 3 mg/m2 should be appropriate. HPPH exposure increases with fat mass while being inversely related to FFM. HPPH-PDT for overweight patients should be monitored with more caution and PDT conditions should be optimized if necessary.

Self-facilitated ROS-responsive nanoassembly of heterotypic dimer for synergistic chemo-photodynamic therapy.

There is an urgent need to develop efficient combination drug delivery approaches to address the low efficiency of clinical cancer monotherapy. However, how to achieve high-efficient synchronous co-delivery and synergistic therapy remains a big challenge. Herein, we report a self-facilitated nanoassembly of a heterotypic chemo-photodynamic dimer for multimodal cancer therapy. A reactive oxygen species (ROS)-responsive dimer of paclitaxel (PTX) and pyropheophorbide a (PPa) is rationally designed and synthesized. The "Two-in-One" dimer serves as both carrier material and cargo, could self-assemble into nanoparticles in water with ultrahigh co-loading capacity and self-facilitated ROS-responsive drug release. The endogenous ROS overproduced in tumor cells together with PPa-generated ROS under laser irradiation synergistically facilitate on-demand drug release from the nano-assembly. The disintegration of nanoassembly triggered by ROS effectively addresses the dilemma of aggregation-caused quenching (ACQ) effect of photosensitizer (PPa). Both in vitro and in vivo results suggest that PTX-initiated chemotherapy in combination with PPa-mediated PDT exhibits synergistic antitumor activity. Our findings provide a strategy for the rational design of nanocarrier for high-efficient synergetic cancer therapy.

A surfactant-like chemotherapeutic agent as a nanocarrier for delivering photosensitizers against cancer: A facile drug-delivering-drug strategy.

Photosensitizer-based photodynamic therapy (PDT) has attracted great attention in cancer treatment. However, achieving efficient delivery of photosensitizers is still a great challenge for their clinical applications. The photosensitizer-encapsulating delivery nanosystem usually suffers from poor stability, complex preparation process and low drug loading. Herein, we utilize a surfactant-like chemotherapeutic agent, mitoxantrone (MTX), as a nanocarrier to deliver a photosensitizer pyropheophorbide a (PPa) for antitumor therapy. MTX consists of aromatic rings (hydrophobic part) and two amino-groups and two hydroxyl-groups (hydrophilic part) with planar structure, which could interact with PPa via π-π stacking, hydrophobic interactions, intermolecular hydrogen bonding and electrostatic interactions. This system (PPa@MTX) spontaneously forms near-spherical nanostructures (∼150 nm), has a high loading capacity for PPa (56.5%) and exhibits a pH-responsive drug release manner in vitro. In vivo antitumor efficacy evaluations show that the pegylated PPa@MTX nanosystem has increased accumulation in tumor tissues and enhanced antitumor efficacy in female BALB/c mice bearing murine mammary carcinoma (4T1) tumor cells, compared to free PPa. Employing the surfactant-like drug as nanocarriers, our results show that the "drug-delivering-drug" strategy is a good foundation for the development of novel PDT-based drug delivery system against cancer.

Folate-Targeted Polyethylene Glycol-Modified Photosensitizers for Photodynamic Therapy.

Pyropheophorbide a (Pyro) is a promising photosensitizer; however, it has no tumor selectivity and enrichment capability. In our former work, the prepared folic acid (FA)-Pyro conjugates showed considerably improved tumor accumulation and photodynamic therapy (PDT) activity in cell- and animal-based studies. However, the targeting capability, selectivity and water solubility of the conjugate remain problematic. Here, we evaluated the installation of hydrophilic polyethylene glycol chains as the linker between Pyro and FA, by avoiding direct conjugation of Pyro with FA, aiming to improve tumor selectivity and accumulation. However, PEGylation may have negative effects on the PDT activity and cutaneous phototoxicity. Therefore, we chose various lengths of PEGs as linkers to optimize the molecular weight, hydrophilicity, and PDT activity and, thus, to balance the tumor selectivity and biological function of the conjugate. One optimized conjugate, Pyro-PEG1K-FA, exhibited excellent tumor enrichment and was able to eradicate subcutaneous tumors at a considerably reduced dose. We report the synthesis and characterization of these conjugates as well as the evaluation of their tumor accumulation ability and the corresponding PDT efficiency through in vitro and in vivo experiments.

Development and application of a physiologically based pharmacokinetic model for HPPH in rats and extrapolate to humans.

2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, is employed in photodynamic therapy (PDT) for the treatment of various malignant lesions. PDT is a drug-device combined targeted treatment, and the clinical responses depend to a large extent on the photosensitizer distribution in target tissues and light exposure. In the present study, we aimed to give some suggestion for the development of HPPH-PDT from the perspective of photosensitizer biodistribution. For the first time, a PBPK model of HPPH was developed, which adequately described HPPH concentration-time profiles in rats plasma and various tissues. The rat PBPK model was further extrapolated to simulate the HPPH disposition in mouse and human. The simulated HPPH human serum concentrations yield a satisfactory agreement with observations at multiple dosing levels. It turned out that overweight may have a significant influence on HPPH exposure in human. Model simulated concentration-time profiles in human target tissues were also obtained. The appropriate time window to conduct light exposure for the treatment of digestive cancer and skin cancer could be 24-48 h and 48-96 h post-dose, respectively. Model simulations can explain the relevant clinical responses to some extent. The incorporation of the PBPK model into PDT could provide the photosensitizer concentrations not only in blood but also in target tissues, which may accelerate the development of this kind of treatment.

Pre-clinical compartmental pharmacokinetic modeling of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) as a photosensitizer in rat plasma by validated HPLC method.

A second-generation chlorin-based photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) has shown tremendous therapeutic potential in clinical trials in the treatment of esophageal cancer. Herein, we have developed and validated a bioanalytical method for estimation of HPPH in rat plasma using High Performance Liquid Chromatography (HPLC) with a photo diode array (PDA) detector. The method was applied for carrying out pharmacokinetic study of HPPH. Further pharmacokinetic modeling was carried out to understand the compartment kinetics of HPPH. The developed method was fully validated as per the United States Food and Drug Administration (US-FDA) guidelines for bioanalytical method validation. The linearity of the method was in the range of 250-8000 ng mL-1, and the plasma recovery was found to be 70%. Pharmacokinetic parameters were evaluated and compared via non-compartment analysis and compartment modeling after the intravenous (i.v.) bolus administration in rats using Phoenix WinNonlin 8.0 (Certara™, USA). From the obtained results, we hypothesize that the HPPH complies with two compartmental pharmacokinetic model. Furthermore, it was observed that HPPH has the rapid distribution from the central compartment to peripheral compartment along with slow elimination from peripheral compartment.

Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent.

We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve the pharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatment efficacy.

First-Pass Metabolism of Chlorophylls in Mice.

SCOPE: The dietary intake of chlorophylls is estimated to be ≈50 mg d-1 . However, their first pass metabolism and systemic assimilation is not well characterized. METHODS AND RESULTS: A group of 30 mice are fed a diet rich in chlorophylls, while 10 mice received a standard diet without chlorophylls (control group). Liver extracts are analyzed every 15 days by HPLC-ESI(+)/APCI(+)-hrTOF- MS/MS to measure the accretion of specific chlorophyll metabolites. The chlorophyll profile found in the livers of mice fed a chlorophyll-rich diet shows that the formation and/or absorption of pheophorbides, pyro-derivatives, and phytyl-chlorin e6 require the occurrence of a precise first-pass metabolism. In addition, the apical absorption of pheorphorbide a-rich micelles is significantly inhibited in Caucasian colon adenocarcinoma-2 cells pre-incubated with BLT1. CONCLUSION: Pheophorbide a absorption is, at least partly, protein-mediated through SR-BI. This active absorption process could explain the specific accumulation of pheophorbide a in the livers of animals fed a chlorophyll-rich diet. A complementary mechanism could be the de-esterification of pheophytin a in the liver, yielding pheophorbide a and phytol, which can explain the origin of phytol in the liver. Hence, the results suggest two molecular mechanisms responsible for the accumulation of the health-promoting compounds pheophorbide and phytol.

N-(2-hydroxypropyl)methacrylamide polymer conjugated pyropheophorbide-a, a promising tumor-targeted theranostic probe for photodynamic therapy and imaging.

Tumor-targeted photodynamic therapy (PDT) using polymeric photosensitizers is a promising therapeutic strategy for cancer treatment. In this study, we synthesized a pHPMA conjugated pyropheophorbide-a (P-PyF) as a cancer theranostic agent for PDT and photodynamic diagnostics (PDD). Pyropheophorbide-a has one carboxyl group which was conjugated to pHPMA via amide bond yielding the intended product with high purity. In aqueous solutions, P-PyF showed a mean particle size of ∼200 nm as it forms micelle which exhibited fluorescence quenching and thus very little singlet oxygen (1O2) production. In contrast, upon disruption of micelle strong fluorescence and 1O2 production were observed. In vitro study clearly showed the PDT effect of P-PyF. More potent 1O2 production and PDT effect were observed during irradiation at ∼420 nm, the maximal absorbance of pyropheophorbide-a, than irradiation at longer wavelength (i.e., ∼680 nm), suggesting selection of proper absorption light is essential for successful PDT. In vivo study showed high tumor accumulation of P-PyF compared with most of normal tissues due to the enhanced permeability and retention (EPR) effect, which resulting in superior antitumor effect under irradiation using normal xenon light source of endoscope, and clear tumor imaging profiles even in the metastatic lung cancer at 28 days after administration of P-PyF. On the contrary irradiation using long wavelength (i.e., ∼680 nm), the lowest Q-Band, exhibited remarkable tumor imaging effect with little autofluorescence of background. These findings strongly suggested P-PyF may be a potential candidate-drug for PDT/PDD, particularly using two different wavelength for treatment and detection/imaging, respectively.

Folate-modified PLGA nanoparticles for tumor-targeted delivery of pheophorbide a in vivo.

Targeted drug delivery has been an important issue for tumor therapy including photodynamic therapy (PDT). The purpose of our study is to increase the targeting efficiency of photosensitizer (PS) using folate-modified nanoparticles (NPs) to tumor site in vivo. Folate receptor is over-expressed on the surface of many human cancer cells. We prepared poly (lactic-co-glycolic acid) (PLGA) NPs containing pheophorbide a (Pba), a PS that is used in PDT and generates free radical for killing cancer cells. The surface of NPs was composed of phospholipids modified with polyethylene glycol (PEG) and folate (FA). The size of the resulting FA-PLGA-Pba NPs was about 200 nm in PBS at pH 7.4 and they were stable for long time. They showed faster cellular uptake to MKN28 human gastric cancer cell line than control PLGA-Pba NPs by high-affinity binding with folate receptors on cell surface. In MTT assay, FA-PLGA-Pba NPs also showed enhanced tumor cell killing compared to control PLGA-Pba NPs. In vivo and ex vivo imaging showed high accumulation of FA-PLGA-Pba NPs in tumor site during 24 h after intravenous injection to MKN28 tumor-bearing mice model. These results demonstrate that our FA-PLGA-Pba NPs are useful for tumor-targeted delivery of PS for cancer treatment by PDT.

A polymer-free, biomimicry drug self-delivery system fabricated via a synergistic combination of bottom-up and top-down approaches.

Compared to conventional carrier-assistant drug delivery systems (DDSs), drug self-delivery systems (DSDSs) have advantages of unprecedented drug loading capacity, minimized carrier-related toxicity and ease of preparation. However, the colloidal stability and blood circulation time of DSDSs still need to be improved. Here we report on the development of a novel biomimicry drug self-delivery system by the integration of a top-down cell membrane complexing technique into our self-delivery multifunctional nano-platform made from bottom-up approach that contains 100% active pharmaceutical ingredients (API) of Pheophorbide A and Irinotecan conjugates (named PI). Compared to conventional cell membrane coated nanoparticles with polymer framework as core and relatively low drug loading, this system consisting of red blood cell membrane vesicles complexed PI (RBC-PI) is polymer-free with up to 50% API loading. RBC-PI exhibited 10 times higher area under curve in pharmacokinetic study and much lower macrophage uptake compared with the parent PI nanoparticles. RBC-PI retained the excellent chemophototherapeutic effects of the PI nanoparticles, but possessed superior anti-cancer efficacy with prolonged blood circulation, improved tumor delivery, and enhanced photothermal effects in animal models. This system represents a novel example of using cell membrane complexing technique for effective surface modification of DSDSs. This is also an innovative study to form a polymer-free cell membrane nanoparticle complexing with positive surface charged materials. This biomimicry DSDS takes advantages of the best features from both systems to make up for each other's shortcomings and posed all the critical features for an ideal drug delivery system.

Intracellular "activated" two-photon photodynamic therapy by fluorescent conveyor and photosensitizer co-encapsulating pH-responsive micelles against breast cancer.

The application of photodynamic therapy (PDT) for the diagnosis and treatment of cancer is hindered by the intrinsic defects of the currently available photosensitizers (PSs), such as poor water solubility and limited light-penetration depth. In this study, pH-responsive polymeric micelles that co-encapsulate therapeutic PSs and organooxotin two-photon compounds were applied for two-photon PDT (TP-PDT) against breast cancer. The TP-PDT effect of the drug-loaded micelles was "activated" when the micelles turned into aggregates at a triggering pH level. The in vitro therapeutic effect was evaluated on 4T1 murine breast cancer cells by viability assays, real-time morphology collapsing, and reactive oxygen species determination. Time-dependent ex vivo organ distribution and in vivo anticancer efficacy results suggested that the drug carriers could accumulate in tumors and suppress tumor growth by TP-PDT. The delivery system could enhance the solubility and distribution of PSs and, if administered along with a tissue-penetrating prolonged light source, could thus have good potential for cancer therapy.

Folic Acid-Conjugated Pyropheophorbide a as the Photosensitizer Tested for In Vivo Targeted Photodynamic Therapy.

Photodynamic therapy (PDT) is a highly localized and minimally invasive cancer treatment modality with many important advantages, but the lack of ideal photosensitizers (PSs) greatly restricts its clinical utility. To develop new PSs with highly efficient singlet oxygen production and high tumor-localizing ability to reduce damage to healthy adjacent tissues, we conjugated folic acid (FA) with pyropheophorbide a (Pyro), a potent PS with a very high singlet oxygen quantum yield and a high extinction coefficient. In the present work, we describe the synthesis and PDT evaluation of this FA-Pyro conjugate both in vitro and in vivo. This conjugation increased the accumulation of Pyro inside the tumors and improved the efficiency of PDT, resulting in eradication of subcutaneous xenograft KB (human mouth epidermal carcinoma) tumors after only 1 or 2 applications of external near infrared light irradiation. This outstanding PDT outcome in a tumor-bearing mouse model and the simple synthesis of the conjugate should have very good practical potential for clinical application.

Photosensitizer-mediated mitochondria-targeting nanosized drug carriers: Subcellular targeting, therapeutic, and imaging potentials.

Mitochondria-targeting drug carriers have considerable potential because of the presence of many molecular drug targets in the mitochondria and their pivotal roles in cellular viability, metabolism, maintenance, and death. To compare the mitochondria-targeting abilities of triphenylphosphonium (TPP) and pheophorbide a (PhA) in nanoparticles (NPs), this study prepared mitochondria-targeting NPs using mixtures of methoxy poly(ethylene glycol)-(SS-PhA)2 [mPEG-(SS-PhA)2 or PPA] and TPP-b-poly(ε-caprolactone)-b-TPP [TPP-b-PCL-b-TPP or TPCL], which were designated PPAn-TPCL4-n (0≤n≤4) NPs. With increasing TPCL content, the formed PPAn-TPCL4-n NPs decreased in size from 33nm to 18nm and increased in terms of positive zeta-potentials from -12mV to 33mV. Although the increased TPCL content caused some dark toxicity of the PPAn-TPCL4-n NPs due to the intrinsic positive character of TPCL, the NPs showed strong light-induced killing effects in tumor cells. In addition, the mitochondrial distribution of the PPAn-TPCL4-n NPs was analyzed and imaged by flow cytometry and confocal microscopy, respectively. Thus, the PhA-containing NPs specifically targeted the mitochondria, and light stimulation caused PhA-mediated therapeutic effects and imaging functions. Expanding the capabilities of these nanocarriers by incorporating other drugs should enable multiple potential applications (e.g., targeting, therapy, and imaging) for combination and synergistic treatments.

Sequestration of ubiquitous dietary derived pigments enables mitochondrial light sensing.

Animals alter their physiological states in response to their environment. We show that the introduction of a chlorophyll metabolite, a light-absorbing pigment widely consumed in human diets, to Caenorhabditis elegans results in animals whose fat mass can be modulated by exposure to light, despite the worm consuming the same amount of food. In the presence of the chlorophyll metabolite, exposing the worms to light increased adenosine triphosphate, reduced oxidative damage, and increased median life spans, without an effect on animal reproduction. Mice fed a dietary metabolite of chlorophyll and exposed to light, over several months, showed reductions in systemic inflammation as measured by plasma α-macroglobulin. We propose that dietary chlorophyll metabolites can enable mitochondria to use light as an environmental cue, by absorbing light and transferring the energy to mitochondrial coenzyme Q.