Organic Nanodelivery Systems as a New Platform in the Management of Breast Cancer: A Comprehensive Review from Preclinical to Clinical Studies

Breast cancer accounts for approximately 25% of cancer cases and 16.5% of cancer deaths in women, and the World Health Organization predicts that the number of new cases will increase by almost 70% over the next two decades, mainly due to an ageing population. Effective diagnostic and treatment strategies are, therefore, urgently required for improving cure rates among patients since current therapeutic modalities have many limitations and side effects. Nanomedicine is evolving as a promising approach for cancer management, including breast cancer, and various types of organic and inorganic nanomaterials have been investigated for their role in breast cancer diagnosis and treatment. Following an overview on breast cancer characteristics and pathogenesis and challenges of the current treatment strategies, the therapeutic potential of biocompatible organic-based nanoparticles such as liposomes and polymeric micelles that have been tested in breast cancer models are reviewed. The efficacies of different drug delivery and targeting strategies are documented, ranging from synthetic to cell-derived nanoformulations together with a summary of the interaction of nanoparticles with externally applied energy such as radiotherapy. The clinical translation of nanoformulations for breast cancer treatment is summarized including those undergoing clinical trials

Spectroscopic evaluation of QDs encapsulated with a novel biocompatible polymer for cancer diagnosis

Quantum dots (QDs) are new class of fluorescent inorganic nanocrystals which have been used for in vitro and in vivo imaging. Their unique optical properties such as broad excitation spectra, narrow emission spectrum and resistance to photobleaching make them ideal for biological labeling. Sentinel lymph node biopsy is a means of ultra-staging cancer metastasis and is now the standard of care in breast cancer surgery. Localisation of sentinel nodes is also important in the treatment of head and neck cancer. Current tracers for SLN biopsy include the blue dye have various limitations that could be overcome by quantum dots that emit in near infrared range (>700 nm). To safely deliver QDs they must be encapsulated in a biocompatible coating. In this study we encapsulate CdTe QDs with new nanocomposite material based on a silsesquioxane modified poly (carbonate-urea) urethane polymer, and evaluated their spectroscopic properties

Synergy between Photodynamic Therapy and Dactinomycin Chemotherapy in 2D and 3D Ovarian Cancer Cell Cultures

In this study we explored the efficacy of combining low dose photodynamic therapy using a porphyrin photosensitiser and dactinomycin, a commonly used chemotherapeutic agent. The studies were carried out on compressed collagen 3D constructs of two human ovarian cancer cell lines (SKOV3 and HEY) versus their monolayer counterparts. An amphiphilc photosensitiser was employed, disulfonated tetraphenylporphine, which is not a substrate for ABC efflux transporters that can mediate drug resistance. The combination treatment was shown to be effective in both monolayer and 3D constructs of both cell lines, causing a significant and synergistic reduction in cell viability. Compared to dactinomycin alone or PDT alone, higher cell kill was found using 2D monolayer culture vs. 3D culture for the same doses. In 3D culture, the combination therapy resulted in 10 and 22 times higher cell kill in SKOV3 and HEY cells at the highest light dose compared to dactinomycin monotherapy, and 2.2 and 5.5 times higher cell kill than PDT alone. The combination of low dose PDT and dactinomycin appears to be a promising way to repurpose dactinomycin and widen its therapeutic applications

Organic Nanodelivery Systems as a New Platform in the Management of Breast Cancer: A Comprehensive Review from Preclinical to Clinical Studies

Breast cancer accounts for approximately 25% of cancer cases and 16.5% of cancer deaths in women, and the World Health Organization predicts that the number of new cases will increase by almost 70% over the next two decades, mainly due to an ageing population. Effective diagnostic and treatment strategies are, therefore, urgently required for improving cure rates among patients since current therapeutic modalities have many limitations and side effects. Nanomedicine is evolving as a promising approach for cancer management, including breast cancer, and various types of organic and inorganic nanomaterials have been investigated for their role in breast cancer diagnosis and treatment. Following an overview on breast cancer characteristics and pathogenesis and challenges of the current treatment strategies, the therapeutic potential of biocompatible organic-based nanoparticles such as liposomes and polymeric micelles that have been tested in breast cancer models are reviewed. The efficacies of different drug delivery and targeting strategies are documented, ranging from synthetic to cell-derived nanoformulations together with a summary of the interaction of nanoparticles with externally applied energy such as radiotherapy. The clinical translation of nanoformulations for breast cancer treatment is summarized including those undergoing clinical trials

Treatment of 3D In Vitro Tumoroids of Ovarian Cancer Using Photochemical Internalisation as a Drug Delivery Method

Photochemical internalisation (PCI) is a means of achieving spatio-temporal control of cytosolic drug delivery using sub-lethal photodynamic therapy (PDT), with a photosensitiser that can be activated by non-ionising visible light. Various 3D models including those developed at our laboratory, where spheroids are grown in a compressed collagen matrix, have been used for studying anti-cancer drug effects. However, the use of a more biomimetic tumouroid model which consists of a relatively hypoxic central cancer mass surrounded by its microenvironment (stroma) has not yet been explored in either toxicity or phototoxicity studies involving PCI. Here, we examined the efficacy of PCI using a porphyrin photosensitiser and a cytotoxin (Saporin) on ovarian cancer tumouroids, with HEY ovarian cancer cells in the central cancer compartment, and HDF fibroblast cells and HUVEC endothelial cells in the surrounding stromal compartment. The efficacy was compared to tumouroids treated with either Saporin or PDT alone, or no treatment. PCI treatment was shown to be effective in the tumouroids (determined through viability assays and imaging) and caused a considerable decrease in the viability of cancer cells both within the central cancer mass and those which had migrated into the stroma, as well as a reduction in the cell density of surrounding HUVEC and HDFs. Post-treatment, the mean distance of stromal invasion by cancer cells from the original cancer mass following treatment with Saporin alone was 730 μm vs. 125 μm for PCI. PDT was also effective at reducing viability in the central cancer mass and stroma but required a higher photosensitiser dose and light dose than PCI. Tumouroids, as tissue mimics, are suitable models for interrogating multicellular events following pharmacological assault

Fluorescence lifetime imaging and FRET-induced intracellular redistribution of tat-conjugated quantum dot nanoparticles through interaction with a phthalocyanine photosensitiser

The interaction of Tat-conjugated PEGylated CdSe/ZnS quantum dots (QD) with the amphiphilic disulfonated aluminium phthalocyanine photosensitiser is investigated in aqueous solution and in a human breast cancer cell line. In aqueous solution, the QDs and phthalocyanine form stable nanocomposites. Using steady-state and time-resolved fluorescence measurements combined with singlet oxygen detection, efficient Förster resonance energy transfer (FRET) is observed with the QDs acting as donors, and the phthalocyanine photosensitiser, which mediates production of singlet oxygen, as acceptors. In cells, the Tat-conjugated QDs localise in lysosomes and the QD fluorescence lifetimes are close to values observed in aqueous solution. Strong FRET-induced quenching of the QD lifetime is observed in cells incubated with the nanocomposites using fluorescence lifetime imaging microscopy (FLIM). Using excitation of the QDs at wavelengths where phthalocyanine absorption is negligible, FRET-induced release of QDs from endo/lysosomes is confirmed using confocal imaging and FLIM, which is attributed to photooxidative damage to the endo/lysosomal membranes mediated by the phthalocyanine acceptor

Cellular Imaging and Time-Domain FLIM Studies of Meso-Tetraphenylporphine Disulfonate as a Photosensitising Agent in 2D and 3D Models

Fluorescence lifetime imaging (FLIM) and confocal fluorescence studies of a porphyrinbased photosensitiser (meso-tetraphenylporphine disulfonate: TPPS2a) were evaluated in 2D monolayer cultures and 3D compressed collagen constructs of a human ovarian cancer cell line (HEY). TPPS2a is known to be an effective model photosensitiser for both Photodynamic Therapy (PDT) andPhotochemical Internalisation (PCI). This microspectrofluorimetric study aimed firstly to investigate the uptake and subcellular localisation of TPPS2a, and evaluate the photo-oxidative mechanism using reactive oxygen species (ROS) and lipid peroxidation probes combined with appropriate ROS scavengers. Light-induced intracellular redistribution of TPPS2a was observed, consistent with rupture of endolysosomes where the porphyrin localises. Using the same range of light doses, time-lapse confocal imaging permitted observation of PDT-induced generation of ROS in both 2D and 3D cancer models using fluorescence-based ROS together with specific ROS inhibitors. In addition, the use of red light excitation of the photosensitiser to minimise auto-oxidation of the probes was investigated.In the second part of the study, the photophysical properties of TPPS2a in cells were studied using a time-domain FLIM system with time-correlated single photon counting detection. Owing to the high sensitivity and spatial resolution of this system, we acquired FLIM images that enabled the fluorescence lifetime determination of the porphyrin within the endolysosomal vesicles. Changes in the lifetime dynamics upon prolonged illumination were revealed as the vesicles degraded within the cells

In vivo biodistribution studies and ex vivo lymph node imaging using heavy metal-free quantum dots

AbstractQuantum dots (QDs) are attractive photoluminescence probes for biomedical imaging due to their unique photophysical properties. However, the potential toxicity of QDs has remained a major obstacle to their clinical use because they commonly incorporate the toxic heavy metal cadmium within the core of the QDs. In this work, we have evaluated a novel type of heavy metal-free/cadmium-free and biocompatible QD nanoparticles (bio CFQD® nanoparticles) with a good photoluminescence quantum yield. Sentinel lymph node mapping is an increasingly important treatment option in the management of breast cancer. We have demonstrated their potential for lymph node mapping by ex vivo imaging of regional lymph nodes after subcutaneous injection in the paw of rats. Using photoluminescence imaging and chemical extraction measurements based on elemental analysis by inductively coupled plasma mass spectroscopy, the quantum dots are shown to accumulate quickly and selectively in the axillary and thoracic regional lymph nodes. In addition, lifetime imaging microscopy of the QD photoluminescence indicates minimal perturbation to their photoluminescence properties in biological systems