Development of PDT/PET theranostics: synthesis and biological evaluation of an ¹⁸F-radiolabeled water soluble porphyrin

Synthesis of the first water-soluble porphyrin radiolabeled with fluorine-18 is described: a new molecular theranostic agent which integrates the therapeutic selectivity of photodynamic therapy (PDT) with the imaging efficacy of positron emission tomography (PET). Generation of the theranostic was carried out through the conjugation of a cationic water-soluble porphyrin bearing an azide functionality to a fluorine-18 radiolabeled prosthetic bearing an alkyne functionality through click conjugation, with excellent yields obtained in both cold and hot synthesis. Biological evaluation of the synthesized structures shows the first example of an 18 F-radiolabeled porphyrin retaining photocytotoxicity following radiolabeling and demonstrable conjugate uptake and potential application as a radiotracer in vivo. The promising results gained from biological evaluation demonstrate the potential of this structure as a clinically relevant theranostic agent, offering exciting possibilities for the simultaneous imaging and photodynamic treatment of tumors

Theranostic Agent Combining Fullerene Nanocrystals and Gold Nanoparticles for Photoacoustic Imaging and Photothermal Therapy

Developing photoactivatable theranostic platforms with integrated functionalities of biocompatibility, targeting, imaging contrast, and therapy is a promising approach for cancer diagnosis and therapy. Here, we report a theranostic agent based on a hybrid nanoparticle comprising fullerene nanocrystals and gold nanoparticles (FGNPs) for photoacoustic imaging and photothermal therapy. Compared to gold nanoparticles and fullerene crystals, FGNPs exhibited stronger photoacoustic signals and photothermal heating characteristics by irradiating light with an optimal wavelength. Our studies demonstrated that FGNPs could kill cancer cells due to their photothermal heating characteristics in vitro. Moreover, FGNPs that are accumulated in tumor tissue via the enhanced permeation and retention effect can visualize tumor tissue due to their photoacoustic signal in tumor xenograft model mice. The theranostic agent with FGNPs shows promise for cancer therapy

A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities

Design principles governing the development of theranostic anticancer agents and their nanoformulations with photoacoustic properties

The unmet need to develop novel approaches for cancer diagnosis and treatment has led to the evolution of theranostic agents, which usually include, in addition to the anticancer drug, an imaging agent based mostly on fluorescent agents. Over the past few years, a non-invasive photoacoustic imaging modality has been effectively integrated into theranostic agents. Herein, we shed light on the design principles governing the development of theranostic agents with photoacoustic properties, which can be formulated into nanocarriers to enhance their potency. Specifically, we provide an extensive analysis of their individual constituents including the imaging dyes, drugs, linkers, targeting moieties, and their formulation into nanocarriers. Along these lines, we present numerous relevant paradigms. Finally, we discuss the clinical relevance of the specific strategy, as also the limitations and future perspectives, and through this review, we envisage paving the way for the development of theranostic agents endowed with photoacoustic properties as effective anticancer medicines

Liposomes and nanotechnology in drug development: focus on neurological targets

Neurological diseases represent a medical, social, and economic problem of paramount importance in developed countries. Although their etiology is generally known, developing therapeutic interventions for the central nervous system is challenging due to the impermeability of the blood-brain barrier. Thus, the fight against neurological diseases usually struggles "at the gates" of the brain. Flooding the bloodstream with drugs, where only a minor fraction reaches its target therapeutic site, is an inefficient, expensive, and dangerous procedure, because of the risk of side effects at nontargeted sites. Currently, advances in the field of nanotechnology have enabled development of a generation of multifunctional molecular platforms that are capable of transporting drugs across the blood-brain barrier, targeting specific cell types or functional states within the brain, releasing drugs in a controlled manner, and enabling visualization of processes in vivo using conventional imaging systems. The marriage between drug delivery and molecular imaging disciplines has resulted in a relatively new discipline, known as theranostics, which represents the basis of the concept of personalized medicine. In this study, we review the concepts of the blood-brain barrier and the strategies used to traverse/bypass it, the role of nanotechnology in theranostics, the wide range of nanoparticles (with emphasis on liposomes) that can be used as stealth drug carriers, imaging probes and targeting devices for the treatment of neurological diseases, and the targets and targeting strategies envisaged in the treatment of different types of brain pathology

Synthesis of Self-Immolative Rhodamine Based Theranostic Agent

Theranostic agents, a class of molecules that simultaneously serve both a diagnostic and therapeutic function, enable in vivo imaging for early diagnosis and targeted drug delivery within a single entity. Due to recent advances in the synthesis and photophysical properties of the rhodamine scaffold, rhodamine dyes present a promising new direction for theranostic research. Toward the goal of exploring rhodamine dyes as self-immolative prodrugs for theranostic applications, we have synthesized a rhodamine precursor via a telescoped radical bromination/hydrolysis. Upon completion of the full rhodamine synthesis, we will explore and optimize the kinetics of its “turn-on” fluorescence and drug release in vitro

Applications of radiation in photodiagnosis and photodynamic therapy

The application of radiation to porphyrin-based photosensitisers for the purposes of photodiagnosis and photodynamic therapy have been described in an effort to explore combined therapies, which seek to extend the use of photodynamic therapy beyond its traditional applications.A fluorine-18 radiolabelled photosensitiser has been developed to combine photodynamic therapy with positron emission tomography (PET) into a single “theranostic agent”. Synthesis of this novel theranostic agent was carried out through the conjugation of a cationic water-soluble porphyrin bearing an azide moiety to a fluorine-18 radiolabelled PEG chain bearing an alkyne moiety via a copper-catalysed azide-alkyne cycloaddition (CuAAC). A biological evaluation of the theranostic agent was undertaken in vitro, exhibiting good uptake into the HT-29 human cancer cell line. It was the first time a porphyrin labelled with fluorine-18 had been shown to have retained photocytotoxicity following radiolabelling. In vivo evaluation confirmed uptake into neoplastic tissue and demonstrated potential as a radiotracer for (PET).Several suitable nanoparticles were synthesised for the potential to generate visible light under the irradiation of hard X-rays by scintillation pathways. Many of the nanoparticles developed were synthesised for the first-time using microwave-assisted syntheses, which was found to optimise their characteristics and had not previously been tested for their potential as scintillators. An entirely new EuWO4 scheelite morphology was discovered in nanoparticle form, which has not previously been achieved and was found to be a scintillator with good potential.A range of scintillating-nanoparticle photosensitiser conjugates (ScNP-PS) were developed by the functionalisation of scintillating nanoparticles and conjugation to a porphyrin photosensitiser. Preliminary evaluation of conjugates was tested by irradiation using energy of 160 keV, whilst singlet oxygen generation was measured spectrophotometrically using a singlet oxygen probe. All the peptide coupled conjugates displayed 1O2 generation, with the rare earth fluorides La1-xEuxF3 and Lu1-xEuxF3 exhibiting the best results

Developing the next generation of graphene-based platforms for cancer therapeutics: The potential role of reactive oxygen species.

This is the final version of the article. Available from the publisher via the DOI in this record.Graphene has a promising future in applications such as disease diagnosis, cancer therapy, drug/gene delivery, bio-imaging and antibacterial approaches owing to graphene's unique physical, chemical and mechanical properties alongside minimal toxicity to normal cells, and photo-stability. However, these unique features and bioavailability of graphene are fraught with uncertainties and concerns for environmental and occupational exposure. Changes in the physicochemical properties of graphene affect biological responses including reactive oxygen species (ROS) production. Lower production of ROS by currently available theranostic agents, e.g. magnetic nanoparticles, carbon nanotubes, gold nanostructures or polymeric nanoparticles, restricts their clinical application in cancer therapy. Oxidative stress induced by graphene accumulated in living organs is due to acellular factors which may affect physiological interactions between graphene and target tissues and cells. Acellular factors include particle size, shape, surface charge, surface containing functional groups, and light activation. Cellular responses such as mitochondrial respiration, graphene-cell interactions and pH of the medium are also determinants of ROS production. The mechanisms of ROS production by graphene and the role of ROS for cancer treatment, are poorly understood. The aim of this review is to set the theoretical basis for further research in developing graphene-based theranostic platforms.The authors would like to thank the EPSRC CDT in Metamaterials (Grant No. EP/L015331/1 G930207) University of Exeter, United Kingdom, for supporting this work