Neuroprotective Effect of Curcumin-Loaded RGD Peptide-PEGylated Nanoliposomes.

Curcumin is known for its anti-inflammatory, neuroprotective, and antioxidant properties, but its use in biological applications is hindered by its sensitivity to light, oxygen, and temperature. Furthermore, due to its low water solubility, curcumin has a poor pharmacokinetic profile and bioavailability. In this study, we evaluated the potential application of curcumin as a neuroprotective agent encapsulated in RGD peptide-PEGylated nanoliposomes developed from salmon-derived lecithin. Salmon lecithin, rich in polyunsaturated fatty acids, was used to formulate empty or curcumin-loaded nanoliposomes. Transmission electron microscopy, dynamic light scattering, and nanoparticle tracking analysis characterizations indicated that the marine-derived peptide-PEGylated nanoliposomes were spherical in shape, nanometric in size, and with an overall negative charge. Cytotoxicity tests of curcumin-loaded nanoliposomes revealed an improved tolerance of neurons to curcumin as compared to free curcumin. Wild-type SH-SY5Y were treated for 24 h with curcumin-loaded nanoliposomes, followed by 24 h incubation with conditioned media of SH-SY5Y expressing the Swedish mutation of APP containing a high ratio of Aß40/42 peptides. Our results revealed significantly lower Aß-induced cell toxicity in cells pre-treated with RGD peptide-PEGylated curcumin-loaded nanoliposomes, as compared to controls. Thus, our data highlight the potential use of salmon lecithin-derived RGD peptide PEGylated nanoliposomes for the efficient drug delivery of curcumin as a neuroprotective agent.

New Crystal Form of Human Neuropilin-1 b1 Fragment with Six Electrostatic Mutations Complexed with KDKPPR Peptide Ligand.

Neuropilin 1 (NRP1), a cell-surface co-receptor of a number of growth factors and other signaling molecules, has long been the focus of attention due to its association with the development and the progression of several types of cancer. For example, the KDKPPR peptide has recently been combined with a photosensitizer and a contrast agent to bind NRP1 for the detection and treatment by photodynamic therapy of glioblastoma, an aggressive brain cancer. The main therapeutic target is a pocket of the fragment b1 of NRP1 (NRP1-b1), in which vascular endothelial growth factors (VEGFs) bind. In the crystal packing of native human NRP1-b1, the VEGF-binding site is obstructed by a crystallographic symmetry neighbor protein, which prevents the binding of ligands. Six charged amino acids located at the protein surface were mutated to allow the protein to form a new crystal packing. The structure of the mutated fragment b1 complexed with the KDKPPR peptide was determined by X-ray crystallography. The variant crystallized in a new crystal form with the VEGF-binding cleft exposed to the solvent and, as expected, filled by the C-terminal moiety of the peptide. The atomic interactions were analyzed using new approaches based on a multipolar electron density model. Among other things, these methods indicated the role played by Asp320 and Glu348 in the electrostatic steering of the ligand in its binding site. Molecular dynamics simulations were carried out to further analyze the peptide binding and motion of the wild-type and mutant proteins. The simulations revealed that specific loops interacting with the peptide exhibited mobility in both the unbound and bound forms.

Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles.

Glioblastoma (GBM) is the most difficult brain cancer to treat, and photodynamic therapy (PDT) is emerging as a complementary approach to improve tumor eradication. Neuropilin-1 (NRP-1) protein expression plays a critical role in GBM progression and immune response. Moreover, various clinical databases highlight a relationship between NRP-1 and M2 macrophage infiltration. In order to induce a photodynamic effect, multifunctional AGuIX®-design nanoparticles were used in combination with a magnetic resonance imaging (MRI) contrast agent, as well as a porphyrin as the photosensitizer molecule and KDKPPR peptide ligand for targeting the NRP-1 receptor. The main objective of this study was to characterize the impact of macrophage NRP-1 protein expression on the uptake of functionalized AGuIX®-design nanoparticles in vitro and to describe the influence of GBM cell secretome post-PDT on the polarization of macrophages into M1 or M2 phenotypes. By using THP-1 human monocytes, successful polarization into the macrophage phenotypes was argued via specific morphological traits, discriminant nucleocytoplasmic ratio values, and different adhesion abilities based on real-time cell impedance measurements. In addition, macrophage polarization was confirmed via the transcript-level expression of TNFα, CXCL10, CD-80, CD-163, CD-206, and CCL22 markers. In relation to NRP-1 protein over-expression, we demonstrated a three-fold increase in functionalized nanoparticle uptake for the M2 macrophages compared to the M1 phenotype. The secretome of the post-PDT GBM cells led to nearly a three-fold increase in the over-expression of TNFα transcripts, confirming the polarization to the M1 phenotype. The in vivo relationship between post-PDT efficiency and the inflammatory effects points to the extensive involvement of macrophages in the tumor zone.

Functionalized liposomes for targeted breast cancer drug delivery.

Despite the exceptional progress in breast cancer pathogenesis, prognosis, diagnosis, and treatment strategies, it remains a prominent cause of female mortality worldwide. Additionally, although chemotherapies are effective, they are associated with critical limitations, most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance (MDR) cancer cells. Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use, none of which employ active targeting. In this review, we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface, transmembrane and internal cell receptors, enzymes, direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells, e.g., cancer stem cells, cells associated with the tumor microenvironment, etc.

tLyp-1: A peptide suitable to target NRP-1 receptor.

Targeting vascular endothelial growth factor receptor (VEFGR) and its co-receptor neuropilin-1 (NRP-1) is an interesting vascular strategy. tLyp-1 is a tumor-homing and penetrating peptide of 7 amino acids (CGNKRTR). It is a truncated form of Lyp-1 (CGNKRTRGC), which is known to target NRP-1 receptor, with high affinity and specificity. It is mediated by endocytosis via C-end rule (CendR) internalization pathway. The aim of this study is to evaluate the importance of each amino acid in the tLyp-1 sequence through alanine-scanning (Ala-scan) technique, during which each of the amino acid in the sequence was systematically replaced by alanine to produce 7 different analogues. In silico approach through molecular docking and molecular dynamics are employed to understand the interaction between the peptide and its analogues with the NRP-1 receptor, followed by in vitro ligand binding assay study. The C-terminal Arg is crucial in the interaction of tLyp-1 with NRP-1 receptor. Substituting this residue dramatically reduces the affinity of this peptide which is clearly seen in this study. Lys-4 is also important in the interaction, which is confirmed via the in vitro study and the MM-PBSA analysis. The finding in this study supports the CendR, in which the presence of R/K-XX-R/K motif is essential in the binding of a ligand with NRP-1 receptor. This presented work will serve as a guide in the future work pertaining the development of active targeting agent towards NRP-1 receptor.

Importance of Rose Bengal Loaded with Nanoparticles for Anti-Cancer Photodynamic Therapy.

Rose Bengal (RB) is a photosensitizer (PS) used in anti-cancer and anti-bacterial photodynamic therapy (PDT). The specific excitation of this PS allows the production of singlet oxygen and oxygen reactive species that kill bacteria and tumor cells. In this review, we summarize the history of the use of RB as a PS coupled by chemical or physical means to nanoparticles (NPs). The studies are divided into PDT and PDT excited by X-rays (X-PDT), and subdivided on the basis of NP type. On the basis of the papers examined, it can be noted that RB used as a PS shows remarkable cytotoxicity under the effect of light, and RB loaded onto NPs is an excellent candidate for nanomedical applications in PDT and X-PDT.

Residual Microscopic Peritoneal Metastases after Macroscopic Complete Cytoreductive Surgery for Advanced High-Grade Serous Ovarian Carcinoma: A Target for Folate Receptor Targeted Photodynamic Therapy?

Despite conventional treatment combining complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy, residual microscopic peritoneal metastases (mPM) may persist as the cause of peritoneal recurrence in 60% of patients. Therefore, there is a real need to specifically target these mPM to definitively eradicate any traces of the disease and improve patient survival. Therapeutic targeting method, such as photodynamic therapy, would be a promising method for such a purpose. Folate receptor alpha (FRα), as it is specifically overexpressed by cancer cells from various origins, including ovarian cancer cells, is a good target to address photosensitizing molecules. The aim of this study was to determine FRα expression by residual mPM after complete macroscopic CRS in patients with advanced high-grade serous ovarian cancer (HGSOC). A prospective study conducted between 1 June 2018 and 10 July 2019 in a single referent center accredited by the European Society of Gynecological Oncology for advanced EOC surgical management. Consecutive patients presenting with advanced HGSOC and eligible for complete macroscopic CRS were included. Up to 13 peritoneal biopsies were taken from macroscopically healthy peritoneum at the end of CRS and examined for the presence of mPM. In case of detection of mPM, a systematic search for RFα expression by immunohistochemistry was performed. Twenty-six patients were included and 26.9% presented mPM. In the subgroup of patients with mPM, FRα expression was positive on diagnostic biopsy before neoadjuvant chemotherapy for 67% of patients, on macroscopic peritoneal metastases for 86% of patients, and on mPM for 75% of patients. In the subgroup of patients with no mPM, FRα expression was found on diagnostic biopsy before neoadjuvant chemotherapy in 29% of patients and on macroscopic peritoneal metastases in 78% of patients. FRα is well expressed by patients with or without mPM after complete macroscopic CRS in patients with advanced HGSOC. In addition to conventional cytoreductive surgery, the use of a therapeutic targeting method, such as photodynamic therapy, by addressing photosensitizing molecules that specifically target FRα may be studied.

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography.

Due to their very poor prognosis and a fatal outcome, secondary brain tumors are one of the biggest challenges in oncology today. From the point of view of the early diagnosis of these brain micro- and macro-tumors, the sensitivity and specificity of the diagnostic tools constitute an obstacle. Molecular imaging, such as Positron Emission Tomography (PET), is a promising technique but remains limited in the search for cerebral localizations, given the commercially available radiotracers. Indeed, the [18F]FDG PET remains constrained by the physiological fixation of the cerebral cortex, which hinders the visualization of cerebral metastases. Tumor angiogenesis is recognized as a crucial phenomenon in the progression of malignant tumors and is correlated with overexpression of the neuropilin-1 (NRP-1) receptor. Here, we describe the synthesis and the photophysical properties of the new gallium-68 radiolabeled peptide to target NRP-1. The KDKPPR peptide was coupled with gallium-68 anchored into a bifunctional NODAGA chelating agent, as well as Cy5 for fluorescence detection. The Cy5 absorbance spectra did not change, whereas the molar extinction coefficient (ε) decreased drastically. An enhancement of the fluorescence quantum yield (φF) could be observed due to the better water solubility of Cy5. [68Ga]Ga-NODAGA-K(Cy5)DKPPR was radiosynthesized efficiently, presented hydrophilic properties (log D = -1.86), and had high in vitro stability (>120 min). The molecular affinity and the cytotoxicity of this new chelated radiotracer were evaluated in vitro on endothelial cells (HUVEC) and MDA-MB-231 cancer cells (hormone-independent and triple-negative line) and in vivo on a brain model of metastasis in a nude rat using the MDA-MB-231 cell line. No in vitro toxicity has been observed. The in vivo preliminary experiments showed promising results, with a high contrast between the healthy brain and metastatic foci for [68Ga]Ga-NODAGA-K(Cy5)DKPPR.

Multigram-scale HPLC enantioseparation as a rescue pathway for circumventing racemization problem during enantioselective synthesis of ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate.

Racemic ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate is a key synthon for the design of promising therapeutic drugs. It is mainly synthesized from racemic ethyl 2,3-dibromopropionate and 2-aminophenol in presence of K2 CO3 in refluxed acetone. Unfortunately, synthesis of (R)- and (S)-enantiomers using the enantioselective version of this reaction, which should normally be performed with a double SN 2 mechanism, is unsuitable due to a racemization process involving the dehydrobromination of enantiopure ethyl 2,3-dibromopropionate into ethyl 2-bromoacrylate. For the first time, the enantioselective version is studied (ee ≈ 55-66%), and the percentage of racemization process has estimated to around 34-46% after determination of the optimal experimental conditions for analytical HPLC enantioseparation of racemate. The influence of the experimental and purification conditions on the racemization rate is also studied. The results indicate that racemization occurs faster at the beginning of the reaction but the initiation of the double SN 2 process takes place more faster to limit the racemization rate. The study of the influence of experimental conditions (reaction times, temperature, solvent or type of base, etc.) on the degree of racemization of the (R)- enantiomer is performed and shows that despite changes in the experimental conditions, the synthesis of the (R)- enantiomer is always accompanied by a racemization rate which is difficult in reducing. In parallel, (R)- and (S)-enantiomers are obtained in high enantiopurity (ee > 99.5%) by preparative HPLC enantioseparation of racemate on multigram scale and characterized by optical rotation measurements, ECD and UV spectra.

Synthesis of New Water Soluble ß-Cyclodextrin@Curcumin Conjugates and In Vitro Safety Evaluation in Primary Cultures of Rat Cortical Neurons.

Self-aggregation of Curcumin (Cur) in aqueous biological environment decreases its bioavailability and in vivo therapeutic efficacy, which hampers its clinical use as candidate for reducing risk of neurodegenerative diseases. Here, we focused on the design of new Cur- ß-Cyclodextrin nanoconjugates to improve the solubility and reduce cell toxicity of Cur. In this study, we described the synthesis, structural characterization, photophysical properties and neuron cell toxicity of two new water soluble ß-CD/Cur nanoconjugates as new strategy for reducing risks of neurodegenerative diseases. Cur was coupled to one or two ß-CD molecules via triazole rings using CuAAC click chemistry strategy to yield ß-CD@Cur and (ß-CD)2@Cur nanoconjugates, respectively. The synthesized nanoconjugates were found to be able to self-assemble in aqueous condition and form nano-aggregates of an average diameter size of around 35 and 120 nm for ß-CD@Cur and (ß-CD)2@Cur, respectively. The photophysical properties, water solubility and cell toxicity on rat embryonic cortical neurons of the designed nanoconjugates were investigated and compared to that of Cur alone. The findings revealed that both new nanoconjugates displayed better water solubility and in vitro biocompatibility than Cur alone, thus making it possible to envisage their use as future nano-systems for the prevention or risk reduction of neurodegenerative diseases.

Photophysical Properties of Protoporphyrin IX, Pyropheophorbide-a and Photofrin® in Different Conditions.

Photodynamic therapy (PDT) is an innovative treatment of malignant or diseased tissues. The effectiveness of PDT depends on light dosimetry, oxygen availability, and properties of the photosensitizer (PS). Depending on the medium, photophysical properties of the PS can change leading to increase or decrease in fluorescence emission and formation of reactive oxygen species (ROS) especially singlet oxygen (1O2). In this study, the influence of solvent polarity, viscosity, concentration, temperature, and pH medium on the photophysical properties of protoporphyrin IX, pyropheophorbide-a, and Photofrin® were investigated by UV-visible absorption, fluorescence emission, singlet oxygen emission, and time-resolved fluorescence spectroscopies.

Doxorubicin Intracellular Release Via External UV Irradiation of Dextran-g-poly(o-nitrobenzyl acrylate) Photosensitive Nanoparticles.

In the present study, innovative doxorubicin-loaded nanoparticles (NPs) made of a photosensitive poly(o-nitrobenzyl acrylate) (PNBA) hydrophobic matrix and an hydrophilic dextran (Dex) shell were first formulated by the emulsion-solvent evaporation process. Doxorubicin (DOX), a very well-known anticancer drug, was herein chosen as the model. DOX-loaded NPs were successfully produced by covering the hydrophobic PNBA core with Dex chains either physically adsorbed or covalently linked by changing process parameters as the presence of a catalyst (CuBr or CuSO4/ascorbic acid). It was then proved that the neutralization of DOX optimized drug loading. DOX loading and release were independent of the coverage mechanism if the catalyst used to covalently link the shell to the core was correctly chosen. Second, the kinetics of DOX release were investigated by simple diffusion or light irradiation of the NPs. Experiments showed that less than 20% of DOX was released by simple diffusion after 48 h in PBS or DMEM media when 45% of DOX released after only 30 s of light irradiation of the NPs. Finally, the impact of the phototriggered DOX release on cell viability was investigated on various cell lines [Caco-2, HepG2, HCT-116, and HT-29 cells as well as murine macrophages (RAW 264.7)]. Cellular mortality was evaluated to be dependent on the cell lines tested. Our approach provided an improved DOX release toward the human liver cancer cell line, and a high internalization of the PNBA-based NPs into HepG2 cells was observed using fluorescence microscopy.

Design of a Targeting and Oxygen-Independent Platform to Improve Photodynamic Therapy: A Proof of Concept.

Photodynamic therapy (PDT) is a promising technique to treat different kinds of disease especially cancer. PDT requires three elements: molecular oxygen, a photoactivatable molecule called the photosensitizer (PS), and appropriate light. Under illumination, the PSs generate, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen, toxic, which then destroys the surrounding tissues. Even if PDT is used with success to treat actinic keratosis or prostate cancer for example, PDT suffers from two major drawbacks: the lack of selectivity of most of the PSs currently used clinically as well as the need for oxygen to be effective. To remedy the lack of selectivity, targeting the tumor neovessels is a promising approach to destroy the vascularization and cause asphyxia of the tumor. KDKPPR peptide affinity for the neuropilin-1 (NRP-1) receptor overexpressed on endothelial cells has already been proven. To compensate for the lack of oxygen, we focused on photoactivatable alkoxyamines (Alks), molecules capable of generating toxic radicals by light activation. In this article, we describe the synthesis of a multifunctional platform combining three units: a PS for an oxygen-dependent PDT, a peptide to target tumor neovessels, and an Alk for an oxygen-independent activity. The synthesis of the compound was successfully carried out, and the study of its photophysical properties showed that the PS retained its capacity to form singlet oxygen and the affinity tests confirmed the affinity of the compound for NRP-1. Thanks to the electron paramagnetic resonance spectroscopy, a technique of choice for radical investigation, the radicals generated by the illumination of the Alk could be detected. The proof of concept was thus successfully established.

Multiscale Selectivity and in vivo Biodistribution of NRP-1-Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma.

BACKGROUND: Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP). METHODS: The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis. RESULTS: The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 µM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by non-invasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism. CONCLUSION: Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.

Enantiopure ethyl 2,3-dibromopropionate: Enantioselective synthesis vs preparative HPLC enantioseparation of racemate on multigram scale.

Racemic ethyl 2,3-dibromopropionate, commercially available at low price, is a key intermediate used in the synthesis of several heterocycle fragments, which are present in many biologically active compounds. Surprisingly, the enantiomers are not commercially available and have never been described in the literature. In this work, we undertook two different strategies to obtain these enantiomers, which are enantioselective synthesis and preparative HPLC enantioseparation of commercially available racemate on multigram scale. The first strategy has proved inadequate because racemization occurred during the synthesis (ee ≈ 9-50%). Conversely, the second strategy produced a very good enantioseparation of commercially available racemate (ee > 99.5% for both enantiomers) on multigram scale.

Inclusion complex vs. conjugation of hydrophobic photosensitizers with ß-cyclodextrin: Improved disaggregation and photodynamic therapy efficacy against glioblastoma cells.

Self-aggregation of hydrophobic porphyrin-based photosensitizers (PSs) in aqueous biological environment decreases their bioavailability and in vivo therapeutic efficacy, which hampers their clinical use in photodynamic therapy (PDT). In the current study, we explore three new supramolecular systems based of hydrophobic PSs (i.e. 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP) or 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (P1COOH)) non-covalently or covalently attached to ß-CD. The two non-covalent solid inclusion complexes (ß-CD)2/mTHPP and [(ß-CD)/P1COOH]4 are prepared by a new co-precipitation@lyophilization combined method and the covalent conjugate ß-CD-P1 by click chemistry. The binding type effect and effectiveness on the disaggregation in aqueous medium and in vitro PDT efficacy against glioblastoma cancer cells of PSs are investigated for the three ß-CD/PS systems. The findings reveal a remarkable improvement of the disaggregation and in vitro PDT activity of these ß-CD/PS systems compared to the free PSs, except for [(ß-CD)/P1COOH]4 inclusion complex caused by J-type self-aggregation of the inclusion complex in tetrameric form. ß-CD-P1 conjugate shows the higher in vitro PDT efficacy compared to the other ß-CD/PS systems. Overall, the results indicate that the disaggregation in aqueous medium and in vitro PDT activity of hydrophobic PSs can be improved by their binding to ß-CD and the covalent binding is the best approach.

New Targeted Gold Nanorods for the Treatment of Glioblastoma by Photodynamic Therapy.

This study describes the employment of gold nanorods (AuNRs), known for their good reputation in hyperthermia-based cancer therapy, in a hybrid combination of photosensitizers (PS) and peptides (PP). We report here, the design and the synthesis of this nanosystem and its application as a vehicle for the selective drug delivery and the efficient photodynamic therapy (PDT). AuNRs were functionalized by polyethylene glycol, phototoxic pyropheophorbide-a (Pyro) PS, and a "KDKPPR" peptide moiety to target neuropilin-1 receptor (NRP-1). The physicochemical characteristics of AuNRs, the synthesized peptide and the intermediate PP-PS conjugates were investigated. The photophysical properties of the hybrid AuNRs revealed that upon conjugation, the AuNRs acquired the characteristic properties of Pyro concerning the extension of the absorption profile and the capability to fluoresce (Φf = 0.3) and emit singlet oxygen (ΦΔ = 0.4) when excited at 412 nm. Even after being conjugated onto the surface of the AuNRs, the molecular affinity of "KDKPPR" for NRP-1 was preserved. Under irradiation at 652 nm, in vitro assays were conducted on glioblastoma U87 cells incubated with different PS concentrations of free Pyro, intermediate PP-PS conjugate and hybrid AuNRs. The AuNRs showed no cytotoxicity in the absence of light even at high PS concentrations. However, they efficiently decreased the cell viability by 67% under light exposure. This nanosystem possesses good efficiency in PDT and an expected potential effect in a combined photodynamic/photothermal therapy guided by NIR fluorescence imaging of the tumors due to the presence of both the hyperthermic agent, AuNRs, and the fluorescent active phototoxic PS.

Fighting Hypoxia to Improve PDT.

Photodynamic therapy (PDT) has drawn great interest in recent years mainly due to its low side effects and few drug resistances. Nevertheless, one of the issues of PDT is the need for oxygen to induce a photodynamic effect. Tumours often have low oxygen concentrations, related to the abnormal structure of the microvessels leading to an ineffective blood distribution. Moreover, PDT consumes O2. In order to improve the oxygenation of tumour or decrease hypoxia, different strategies are developed and are described in this review: 1) The use of O2 vehicle; 2) the modification of the tumour microenvironment (TME); 3) combining other therapies with PDT; 4) hypoxia-independent PDT; 5) hypoxia-dependent PDT and 6) fractional PDT.

Light-sensitive dextran-covered PNBA nanoparticles to continuously or discontinuously improve the drug release.

In this work, photo-sensitive core/shell nanoparticles (NPs) based on biocompatible dextran-g-poly(o-nitrobenzyl acrylate) copolymers (Dex-g-PNBA), containing dextran as hydrophilic backbone and PNBA as photosensitive grafts, were formulated using two processes. In the first process (nanoprecipitation), NPs were prepared using preformed Dex-g-PNBA copolymers. Using the second process (emulsion/organic solvent evaporation), "clicked" or "unclicked" NPs were obtained carrying out (or not) an interfacial in situ click chemistry, respectively. Two model molecules, Nile Red (NR) and Doxorubicin (DOX), were encapsulated and their controlled release from NPs was investigated under UV irradiations to demonstrate the high potential of such photosensitive NPs in biomedicine applications as drug delivery nanocarriers. According to such irradiations, improved release was easily observed. Release kinetics depended on the formulation process and the NPs core chemistry, but not on the occurrence of the interfacial in situ click chemistry. More interesting, a stepped release of such model molecules may easily be obtained.