Photochemical internalisation (PCI) is a method for enhancing delivery of drugs such as cytotoxins to their intracellular target sites of action through the use of low dose photodynamic therapy (PDT). One of the main applications of PCI is local treatment of solid cancerous tumours. The use of three-dimensional (3D) tissue culture cancer models can provide more physiologically relevant information compared to standard monolayer culture owing to the present of an extracellular matrix. The aim of this study was to examine the effect of PDT and PCI in 3D compressed collagen cancer constructs of breast and ovarian cancer. The use of plastically compressed collagen confers near physiological densities of collagen unlike standard hydrogels. In the first set of PCI studies, a disulfonated porphyrin (TPPS2a) was used as the photosensitiser together with a cytotoxic macromolecule, a ribosome inactivating protein (saporin) to investigate the efficacy of the treatment in spheroid and non-spheroid compressed collagen 3D constructs of breast and ovarian cancer versus conventional 2D culture. Three human cell lines were investigated, a breast cancer cell line (MCF-7) and two ovarian cancer cell lines (SKOV3 and HEY). Using a range of assays including optical imaging, the treatment resulted in significant and synergistic reduction in viability of cells in the 2D and non-spheroid constructs of all 3 cell lines when measured at 48 or 96 hours post-illumination. In a further set of experiments, PCI-induced enhancement in cytotoxicity was observed when Dactinomycin was used as the cytotoxic agent. This is the first time that PCI with Dactinomycin has been investigated. In the larger spheroid constructs of ovarian cancer cells, PCI was still effective but required higher saporin and photosensitiser doses compared to 2D and non-spheroid cultures. PCI treatment was observed to induce death principally by apoptosis in the non-spheroid constructs of ovarian cancer compared to the mostly necrotic cell death caused by PDT. At low oxygen levels (1%) both PDT and PCI were significantly less effective in the constructs compared to 2D models. Using the 3D tumouroid model, where a central cancer mass is surrounded by the collagen matrix populated by fibroblasts to simulate the stroma, PCI was found to be able to both kill ovarian cancer cells within the cancer mass and inhibit their migration to the stroma. In conclusion, the use of 3D cancer models provides a useful means to assess the efficacy of PCI for the minimally invasive treatment of breast and ovarian cancer prior to in vivo studies and could help reduce the number of animals used in animal experimentation.

Minimally invasive techniques such as Photodynamic Therapy (PDT) and Photochemical Internalisation (PCI) have for years been under investigation for the treatment of solid cancers. A significant number of the recent research studies have applied PDT and PCI to biological three-dimensional (3D) cancer platforms with many of the studies also involving the use of nanoparticles in order to enhance the efficacy of these light-based therapies. Interest in the employment of 3D cancer platforms has increased considerably due to the ability of the platforms to mimic in vivo models better than the conventional two-dimensional (2D) cultures. Some of the advantages of the 3D cancer systems over their 2D counterparts include improved interaction between cancer cells and the surrounding extracellular matrix (ECM) as well as restricted drug penetration which would allow optimization of treatments prior to undertaking of in vivo studies. The different chapters of this book will discuss photosensitizers and nanoparticles used in PDT and PCI in addition to the applications of these treatments in various 3D cancer models.

Dr. Davide Staedler is CEO of TIBIO Sagl, a consulting company, and chief scientific officer of Scitec Research S.A., a private analytical laboratory. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

In vitro studies showed a preferential affinity of the smart packaged system to ovarian carcinoma cell line OV2008 as compared to normal epithelial cell lines of Ilow and MCC3. Further, feasibility of the drug delivery system was evaluated in vivo. Toxicity studies revealed that the system was non-toxic and feasible in vivo. The final outcome of this study includes tuning of the variables mentioned above that will contribute to the development of low cost and improved methods for drug delivery with application to intracavitary ovarian cancer treatment and other types of cancer.

This book proposes the importance of new systems of drug design and delivery based on cancer pathophysiology in addition to cancer molecular and cellular biology. The current studies based on molecular and cellular biology while ignoring pathophysiology and pharmacology may be leading the development of antitumor drugs in the wrong direction and wasting a lot of money. Although there have been numerous reports of genetic and phenotypic changes in tumors, a large body of pathological and clinical evidence supports the conclusion that there are no pivotal changes in tumor cells that distinguish them consistently and reliably from normal dividing cells. Unlike using antibiotics against bacterial infection, therefore, anticancer agents (ACAs) need to be delivered selectively to tumor tissues and should be kept there long enough to reproduce the concentrations they reach in the Petri dish, which is a closed space where the cytocidal effects of any anticancer agents (ACAs) including molecular targeting agents are very strong. In the body, however, administered ACAs are cleared with the passage of time. Furthermore, most human cancers possess abundant stroma that hinders the penetration of drugs into the tumor microenvironment. Therefore, to overcome these difficulties, novel drug delivery systems have been designed, such as nanoparticles and ACA conjugated antibodies to stromal components and to cancer cell surface antigens. These advances are described in this book after the first section, which describes core features of the pathophysiology of the cancer microenvironment, on which these new developments are based.

Breast cancer remains one of the most diagnosed cancers in women, where 1 in 8 develop breast cancer in the United States. Breast conserving surgeries, radiation and chemotherapy are costly with harmful side effects that can affect the patient years after treatment. To overcome these effects, researchers have investigated polymeric nanoparticles for controlled drug release and cell targeting capabilities. However, current in vivo models do not fully emulate biochemical and biophysical phenomena observed in breast cancer to test the efficacy of drug delivery vehicles. We hypothesize that breast tumor-on-a-chip microfluidic devices can simulate the tumor microenvironment and complex phenomena observed in vivo. In this work, drug-loaded chitosan/polylactide nanoparticles were fabricated and tested for their drug delivery potential in two-dimensional (2D) and tumor-on-a-chip three-dimensional (3D) platforms. Stem cell cytotoxicity, drug encapsulation, in vitro drug release and breast cancer viability after treatment with drug-loaded nanoparticles in 2D and 3D were evaluated.

The present dissertation focuses on formulation design of and in vitro/in vivo characterization of anticancer drug delivery systems for metastatic cancer treatment. There are two aspects to this work: i) formulation design and development of a nanoparticle platform for chemotherapy; and ii) characterization of in situ forming implants for hormone cancer therapy. The main goal of the first aim is to overcome side effects of chemotherapy that are significant concerns in the use of anticancer drugs through cancer active targeting and controlled drug release. A nanoparticle platform equipped with active targeting and pH-responsive functionalities was engineered using biocompatible materials with simple preparation methods, which may facilitate the development of nanoparticle drug products for cancer therapy. Nanoparticle uptake, therapeutic efficacy, and cytotoxicity were investigated using metastatic cancer cell models to evaluate anticancer performance of the nanoparticles. The main goal of the second aim is to identify critical factors affecting drug release kinetics of an in situ forming implant formulation. In vitro/in vivo characterization of in situ forming implants were investigated to understand implant formation and drug release mechanism. The characterization demonstrated that implant formation significantly impacts on drug release kinetics of ISFI formulations. A dissolution device was designed and created using 3D printing to generate biorelevant and reproducible drug release profiles of ISFIs. Water-dissolvable PVA films were combined with open window shaped 3D printed devices. This design allows implant formation without exposure to sink conditions. The results demonstrated that the 3D printed devices not only maintain consistent shape and size of ISFI formulations, but also generate reproducible in vitro release profiles. The 3D printed dissolution devices may prove a useful tool bioequivalence studies of ISFI formulations. Moreover, this work reports the first morphological and microstructural demonstration of in situ forming PLGA implants in a rabbit model.

This book was conceived from a simple question as to why cancer is so difficult to treat. Ultimately we want to find ways to cure cancers, but that may be an elusive dream at least with the technologies we have now and expect to have in the near future. This leads the question of whether it is possible to improve current cancer treatment methods, especially from the perspective of enhancing targeted drug delivery to tumors. This volume is designed to provide information related to the difficulties in treating cancers through targeted drug delivery, our current understanding of cancer biology, and potential technologies that might be used to achieve enhanced drug delivery to tumors. An ideal drug delivery system for treating cancers would maximize the therapeutic efficacy with minimal side effects in clinical applications. The seemingly improved anticancer efficacy of the current nanoparticle-based formulations needs to be viewed from the context of very poor success rates for translation to human applications. The results of in vitro cell culture models and small animal in vivo experiments have not been extrapolated to clinical applications. Finding the reasons for the lack of successful translation is required if we are to discover approaches to substantially extend the survival time of cancer patients, and hopefully identify cures. Cancer Targeted Drug Delivery: Elusive Dream describes some answers of achieving the so far elusive dream of treating cancers like other chronic diseases with therapies that focus using improved drug delivery systems designed to better align with the unique biological and physiological properties of cancer.

The 3D printing (3DP) process was patented in 1986; however, only in the last decade has it begun to be used for medical applications, as well as in the fields of prosthetics, bio-fabrication, and pharmaceutical printing. 3DP or additive manufacturing (AM) is a family of technologies that implement layer-by-layer processes in order to fabricate physical models based on a computer aided design (CAD) model. 3D printing permits the fabrication of high degrees of complexity with great reproducibility in a fast and cost-effective fashion. 3DP technology offers a new paradigm for the direct manufacture of individual dosage forms and has the potential to allow for variations in size and geometry as well as control dose and release behavior. Furthermore, the low cost and ease of use of 3DP systems means that the possibility of manufacturing medicines and medical devices at the point of dispensing or at the point of use could become a reality. 3DP thus offers the perfect innovative manufacturing route to address the critical capability gap that hinders the widespread exploitation of personalized medicines for molecules that are currently not easy to deliver. This Special Issue will address new developments in the area of 3D printing and bioprinting for drug delivery applications, covering the recent advantages and future directions of additive manufacturing for pharmaceutical products.