Design and assembly of a nanoparticle, antibody, phthalocyanine scaffold for intracellular delivery of photosensitizer to human papillomavirus-transformed cancer cells.

In photodynamic therapy (PDT), internalization and uptake of the photosensitizer (PS) by the cells is a passive process that relies on the enhanced permeability and retention (EPR) effect of tumour tissues due to their vasculature, increased LDL receptors, and decreased lymphatic drainage in vivo. But as worries about PDT resistance grow, using passive techniques to administer PSs is becoming less and less viable. According to reported resistance mechanisms, it is necessary to improve PS delivery by changing PS absorption and bioavailability in order to enhance the therapeutic outcome. Therefore, in this study, a multifunctional photosensitizing agent with specific monoclonal antibodies (mAbs) to E6 oncoproteins was developed for PDT of human papillomavirus (HPV)-transformed cancer cells. Using PEGylated Gold Nanoparticles (PEGy-AuNP) at the core, anti-E6 mAbs and phthalocyanines were bound together. This compound demonstrated enhanced internalization of PS, resulting in enhanced PDT effects. In spite of being demonstrated in vitro, the substance in this work is intended for in vivo application, and conclusions are drawn to suggest possible outcomes for in vivo models based on observed data. By making PSs more bioavailable, facilitating their entry into cells, and preventing efflux through intracellular binding, this strategy may reduce cellular resistance to PDT.

Enhanced Intracellular Photosensitizer Uptake and Retention by Targeting Viral Oncoproteins in Human Papillomavirus Infected Cancer Cells and Cancer Stem Cells.

Immunogenic proteins in cancer are relevant targets for drug delivery. In Photodynamic Therapy (PDT), surface antigens have previously been used to deliver the photosensitizer (PS) to the tumor microenvironment for specific targeting. However, can we target intracellular antigens to achieve more than surface recognition? Can we possibly increase PS intracellular localization and prevent drug efflux at the same time? In this study, these questions were addressed by using a compound that can not only specifically recognize and bind to intracellular E6 oncoproteins in Human Papillomavirus (HPV)-Transformed cancer cells, but is also capable of enhancing transmembrane uptake using the cells' own active transport mechanisms. HPV-transformed SiHa cells were cultured in vitro, and the resistant subpopulation was isolated using Magnetic Activated Cell Sorting (MACS). PDT was performed on four different cell types with varying physiognomies in terms of HPV oncoprotein expression and physiological form. Results demonstrated that tagging PSs on a carrier molecule that specifically delivers the PS inside the cells that express the target proteins enhanced both cellular uptake and retention of the PS even in the presence of drug efflux proteins on resistant subpopulations. These findings provide insight into the possibility of preventing cell-mediated resistance to PDT.

Biological Therapy with Complementary and Alternative Medicine in Innocuous Integrative Oncology: A Case of Cervical Cancer.

Good medicine is based on good science, inquiry driven and open to new paradigms. For a complex disease such as cancer, a complex treatment regime that is well structured and multifactorial is indispensable. In the present day, Complementary and Alternative Medicine (CAM) therapies are being used frequently for cancer, alongside modern biological therapies and allopathic medicine, in what is called integrative oncology. In all conscience, the use of natural, less invasive interventions whenever possible is ideal. However, a comprehensive understanding of not only the etiopathology of individual cancers, but also the detailed genetic and epigenetic characteristics, the cancer hallmarks, that clearly show the blueprint of the cancer phenotype is a requisite. Different tumors have a common behavioral pattern, but their specific features at the genetic and epigenetic levels vary to a great extent. Henceforth, with so many failed attempts to therapy, drug formulations and combinations need a focused pre-assessment of the inherent features of individual cancers to destroy the tumors holistically by targeting these features. This review therefore presents innocuous therapeutic regimes by means of CAM and integrative medicine approaches that can specifically target the hallmarks of cancer, using the case of cervical cancer.

Nanotechnology in Modern Photodynamic Therapy of Cancer: A Review of Cellular Resistance Patterns Affecting the Therapeutic Response.

Photodynamic therapy (PDT) has emerged as a potential therapeutic option for most localized cancers. Its high measure of specificity and minimal risk of side effects compared to other therapies has put PDT on the forefront of cancer research in the current era. The primary cause of treatment failure and high mortality rates is the occurrence of cancer resistance to therapy. Hence, PDT is designed to be selective and tumor-specific. However, because of complex biological characteristics and cell signaling, cancer cells have shown a propensity to acquire cellular resistance to PDT by modulating the photosensitization process or its products. Fortunately, nanotechnology has provided many answers in biomedical and clinical applications, and modern PDT now employs the use of nanomaterials to enhance its efficacy and mitigate the effects of acquired resistance. This review, therefore, sought to scrutinize the mechanisms of cellular resistance that affect the therapeutic response with an emphasis on the use of nanomaterials as a way of overriding cancer cell resistance. The resistance mechanisms that have been reported are complex and photosensitizer (PS)-specific. We conclude that altering the structure of PSs using nanotechnology is an ideal paradigm for enhancing PDT efficacy in the presence of cellular resistance.

Photodynamic therapy of cervical cancer by eradication of cervical cancer cells and cervical cancer stem cells.

The heterogeneous nature of cancer puts cancer stem cells (CSCs) at the beating heart of the tumour. Because of their inherent characteristics of stemness, CSCs evade putative cancer therapies, resulting in treatment resistance or tumour recurrence after a seemingly successful treatment. To prevent treatment resistance and cancer recurrence, killing the beating heart of the tumour is of utmost importance. This study therefore, sought to determine the effect of Photodynamic Therapy (PDT) in eradicating cervical cancer and cervical CSCs. Cervical CSCs were isolated from a cervical adenocarcinoma cell line, HeLa cells, and grown in liquid medium incubated at 37° C, 5% CO2 and 85% humidity. Increasing doses of AlPcSmix photosensitizer were administered to both the total cell population and the isolated CSCs, and irradiated using 673.2 nm diode laser. Post-irradiation cellular changes were observed using biochemical assays and microscopy to determine the response of both the total cell population and the CSCs. Results showed a dose-dependent response of both cell populations to treatment, by demonstration of significant morphologic changes, increased cytotoxicity, and decreased cell viability and proliferation. The study suggested that PDT using AlPcSmix is a very effective treatment method for the eradication of cervical cancer cells and cervical CSCs, in vitro.