Chapter 13 - Lipids and natural polymer–based carrier systems for photodynamic therapy

In this invited paper, we applied standard methods of evidence synthesis and critical appraisal to summarize the current state of clinical evidence on PDT for the treatment of different types of cancers. A total of 266 studies spanning 11,427 patients and 34 different types of cancer were reviewed. Forty-four were comparative and 222 were non-comparative. The majority of comparative studies did not assess PDT versus conventional therapy. Therefore, it was not possible to determine the incremental benefit of treatment with PDT. Most of the non-comparative studies involved small, mixed patient populations and short follow-up periods. Consequently, the quality of evidence accumulated to date was considered to be low. Well-defined, prospective, comparative trials of PDT, alone, versus conventional therapies are needed in order to determine its clinical effectiveness.

Photodynamic Therapy (PDT) has become one of the most promising treatment against autoimmune diseases, such as rheumatoid arthritis (RA), as well as in the treatment of different types of cancer, since it is a non-invasive method and easy to carry out. The three main ingredients of PDT are light irradiation, oxygen, and a photosensitizer (PS). Light irradiation depends on the type of molecule or compound to be used as a PS. The concentration of O2 fluctuates according to the medium where the target tissue is located and over time, although it is known that it is possible to provide oxygenated species to the treated area through the PS itself. Finally, each PS has its own characteristics, the efficacy of which depends on multiple factors, such as solubility, administration technique, retention time, stability, excitation wavelength, biocompatibility, and clearance, among others. Therefore, it is essential to have a thorough knowledge of the disease to select the best PS for a specific target, such as RA. In this review we will present the PSs used in the last three decades to treat RA under PDT protocol, as well as insights on the relevant strategies.

Photodynamic therapy (PDT) provides an effective therapeutic option for different types of cancer in addition to surgery, radiation, and chemotherapy. The treatment outcome of PDT is largely determined by both the light and dark toxicity of photosensitizers (PSs), which can be technically improved with the assistance of a drug delivery system, especially the nanocarriers. Toluidine blue (TB) is a representative PS that demonstrates high PDT efficacy; however, its application is largely limited by the associated dark toxicity. Inspired by TB’s noncovalent binding with nucleic acids, in this study, we demonstrated that DNA nanogel (NG) could serve as an effective TB delivery vehicle to facilitate anticancer PDT. The DNA/TB NG was constructed by the simple self-assembly between TB and short DNA segments using cisplatin as a crosslinker. Compared with TB alone, DNA/TB NG displayed a controlled TB-releasing behavior, effective cellular uptake, and phototoxicity while reducing the dark toxicity in breast cancer cells MCF-7. This DNA/TB NG represented a promising strategy to improve TB-mediated PDT for cancer treatments.

Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers. PDT is based on a reaction involving a photosensitizer (PS), light, and oxygen, which ultimately generates cytotoxic reactive oxygen species (ROS). However, skin photosensitivity, due to the accumulation of PSs in skin cells, has hampered, among other elements, its clinical development and application. Therefore, these is an increasing interest in the use of (metal-based) PSs that are more specific to tumor cells. This may increase efficacy and corollary decrease side-effects. To this end, metal-containing nanoparticles with photosensitizing properties have recently been developed. In addition, several studies have reported that the use of immunogenic/immunomodulatory metal-based nanoparticles increases the antitumor efficacy of immune-checkpoint inhibitor-based immunotherapy mediated by anti-PD-(L)1 or CTLA-4 antibodies. In this review, we discuss the main metal complexes used as PDT PSs. Lastly, we review the preclinical studies associated with metal-based PDT PSs and immunotherapies. This therapeutic association could stimulate PDT.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

Liver cancer, especially hepatocellular carcinoma (HCC), is an aggressive disease with an extremely high mortality rate. Unfortunately, no promising markers are currently available for the early diagnosis of this disease. Thus, a reliable biomarker reflecting the early behaviour of the tumour will be valuable for diagnosis and treatment. The Ras homologous (Rho) GTPases, which belong to the small guanosine triphosphate (GTP) binding proteins, have been reported to play an important role in mediating liver cancer based on their important function in cytoskeletal reorganisation. These proteins can be either oncogenic or tumour suppressors. They are also associated with the acquirement of malignant features by cancer cells. The overexpression of RhoA and Rac1, members of the Rho GTPases, have been linked with carcinogenesis and the progression of different types of cancer. In the quest of elucidating the role of mechanical stimulation in the mechanobiology of liver cancer cells, this paper evaluates the effect of stretching on the expression levels of RhoA and Rac1 in different types of liver cancers. It is shown that that stretching liver cancer cells significantly increases the expression levels of RhoA and Rac1 in HCC and cholangiocarcinoma cell lines. We hypothesise that this relatively simple and sensitive method could be helpful for screening biological features and provide suitable treatment guidance for liver cancer patients.

Estimation of Life Expectancy and the Expected Years of Life Lost in Patients with Major Cancers: Extrapolation of Survival Curves under High-Censored Rates

CD8+ and CD4+ T-cells play a key role in cellular immune responses against cancer by cytotoxic responses and effector lineages differentiation, respectively. These subsets have been found in different types of cancer; however, it is unclear whether tumor-infiltrating T-cell subsets exhibit similar transcriptome profiling across different types of cancer in comparison with healthy tissue-resident T-cells. Thus, we analyzed the single cell transcriptome of five tumor-infiltrating CD4-T, CD8-T and Treg cells obtained from different types of cancer to identify specific pathways for each subset in malignant environments. An in silico analysis was performed from single-cell RNA-sequencing data available in public repositories (Gene Expression Omnibus) including breast cancer, melanoma, colorectal cancer, lung cancer and head and neck cancer. After dimensionality reduction, clustering and selection of the different subpopulations from malignant and nonmalignant datasets, common genes across different types of cancer were identified and compared to nonmalignant genes for each T-cell subset to identify specific pathways. Exclusive pathways in CD4+ cells, CD8+ cells and Tregs, and common pathways for the tumor-infiltrating T-cell subsets were identified. Finally, the identified pathways were compared with RNAseq and proteomic data obtained from T-cell subsets cultured under malignant environments and we observed that cytokine signaling, especially Th2-type cytokine, was the top overrepresented pathway in Tregs from malignant samples.

Among the great challenges facing the Society is the search for solutions to cancer. This disease presents high cellular oxidative stress, as a result of the imbalance between the oxidizing species generated in the cells and antioxidant compounds. One of the strategies used in the treatment of cancer is based on the use of Photodynamic therapy (PDT). PDT is a safe and non-invasive technique for the treatment of different types of cancer in diverse locations, as well as non-cancer diseases. PDT consists of the local or systemic application of a photosensitive compound (the photosensitizer), which accumulates mainly in the pathological tissues. Photosensitive molecules absorb light of the appropriate wavelength, initiating the activation processes that lead to the selective destruction of tumor cells. An adequate photosensitizer must obey a number of features such as maximum absorption length between 600 and 800 nm, minimum absorption length between 400 and 600 nm, high purity and stability at room temperature, and high selectivity with tumor tissues, among others. In this context, selenopyrylium salts emerge as potential candidates to photosensitizers due to fit with most of these features. Therefore, the aims in the present work are the synthesis and characterization of monocationic selenopyrillium salts, using a methodology that does not involve organometallic reagents, and the evaluation of their photophysical properties for their possible application as photosensitizers in PDT.

Background. The current best predictor of lifetime risk for many forms of cancer is family history. Family history is transmitted through germ line DNA. Analysis of germ-line DNA should be able to predict lifetime risk at least as well family history. Genetic risk scores, used to predict lifetime risk from DNA, usually consist of linear combinations of SNPs. These scores ignore structural variations and epistatic effects (non-linear combinations). The objective of this study is to test whether germline DNA structural information along with machine learning algorithms, which can use non-linear combinations, can be used to predict whether a person will develop different types of cancer. Methods. We tested this objective using data compiled by The Cancer Genome Atlas (TCGA) project and the UK Biobank. The TCGA data consisted of information on DNA chromosome scale length variation extracted from the peripheral blood of 8,821 different patients, each of whom had one of 32 different types of cancer. The UK Biobank data consisted of about 1500 women diagnosed with breast cancer (cases) and about 5000 women who have no record of any type of cancer(controls). We characterized structural variation by a quantitative measure of chromosomal-scale length variation. Chromosomal-scale length variation is computed from array data. A person's DNA (chromosomes 1-22) can be characterized by a series of 22 numbers, each representing the log base 2 ratio of the chromosome's length compared to the average chromosome length. Using these 22 numbers for each person, we set up a machine learning classification problem to differentiate those people diagnosed with a particular form of cancer from those who have not been diagnosed with that cancer. We used the h2o libraries in R to test how well different machine-learning algorithm can classify with these datasets. Results. In two independent datasets, the Cancer Genome Atlas (TCGA) project and the UK Biobank, we could classify whether or not a patient had a certain cancer based solely on chromosomal scale length variation. We found that all 32 different types of cancer in the TCGA dataset tested could be predicted better than chance using structural variation data. Specifically, in the TCGA dataset we measured the area under the receiver operator curve, known as the AUC, for ovarian cancer in women (0.89), glioblastoma multiforme (0.86), breast cancer in women (0.75), and colon adenocarcinoma (0.79), with a 95% confidence interval width of less than 0.01 in each case. This method could predict 10% of glioblastoma multiforme cases with less than 1 in 10,000 false positives in the TCGA dataset. In the UK Biobank dataset, we could predict breast cancer in women with an AUC=0.83. Conclusion. Genetic risk scores based on structural variation can effectively predict whether a person will eventually develop may different types of cancer. Citation Format: Chris Toh, Charmeine Ko, James P. Brody. Genetic risk scores from structural variation predict life-time individual cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2317.

Analysis of ROS dynamics based on dissolved oxygen sensing in upconversion nanoparticle-based photodynamic therapy.

In recent years, photodynamic therapy (PDT) has been approved for treating various medical conditions, including pre-cancer and cancer. PDT is a treatment that employs particular drugs, called ‘photosensitizers (PS)' which work along with the specific light source and local oxygen in the treated area. The significant benefits of PDT are minimally invasive procedures while delivering high accuracy in targeting areas. In the past two decades, cancer researchers have conducted remarkable studies developing photosensitizers that have enhanced our understanding in the fields of cancer biology and its genetics. However, several limitations of PDT have been noticed, such as skin photosensitivity and inefficient PDT efficacy under hypoxia conditions. Besides this, the stability and solubility of photosensitizer in aqueous solution is another crucial factor for efficient PDT activity. The glycosylation of photosensitizers would be a potential strategy to overcome the limitations of PDT described above. Thus, this mini-review is focused primarily on the molecular design and biological applications of glycosylated photosensitizers, which can provide new ways of designing them.

The purpose of the study is to find out the overall incidence of superscan among different type of cancers, causes of superscan and its relationship with other parameters such as age, sex, duration of disease, and serum alkaline phosphatase (ALP) levels. This was a retro-prospective study. Records of all previous bone scans and reported patients of superscan were re-evaluated retrospectively. Patients who were diagnosed as having superscan in the preceding 3 years with confirmed histopathological diagnosis were included in the retrospective group. In the prospective group, all the patients who were reported to have superscan appearance over the past 2 years of prospective period were included. Total of 6027 bone scans were examined in a 5-year period and out of which 80 cases were diagnosed as superscan. The overall incidence of superscan in different type of cancers was 1.3% (80/6027). Prostate cancer (46/80) was the most common cause of superscan appearance followed by breast cancer (10/80). Out of 6027 patients referred for bone scan, 307 patients had prostate cancer on histopathological examination. Out of 307 patients with prostate cancer, 46 had superscan appearance. Incidence of superscan in prostate cancer was 14.98% (46/307), and 71.73% (33/46) prostate cancer patients with superscan had Gleason score of 8 and above 8 with mean serum prostate-specific antigen level was 178.42 ng/ml in symptomatic patients and 122 ng/ml in asymptomatic patients. Out of all patients with superscan, 71 patients (88.7%) had elevated serum ALP levels. Overall incidence of superscan in our study was 1.3% in different type of cancer patients, and the most common cause of superscan appearance was prostate cancer. Incidence of superscan appearance in prostatic cancer patients was 14.98%.

In recent years,photodynamic therapy (PDT) has emerged as a potentialantibacterial and anticancer alternative. The free radicals are generatedin the presence of photosensitizers (PS) and oxygen under light irradiationof a specific wavelength, causing cytotoxic damage to the cells. Ruthenium­(II)photosensitizers (Ru­(PS)) are of interest due to their rich photochemicalproperties and potential antibacterial and anticancer activities reportedin previous studies. However, the low uptake by bacterial and cancercells has limited the clinical uses of Ru­(PS). In this study, thepotential of membrane-targeting peptides involving arginine-tryptophan(Arg-Trp or RW) in enhancing the uptake of the Ru­(PS), namely, RuCOOH,into bacterial and cancer cells, as well as their antibacterial andanticancer efficiencies, has been studied. The minimum inhibitoryconcentrations (MICs) of compounds against eight bacteria, including Staphylococcus aureus (SA), Acinetobacterbaumannii (AB), Pseudomonas aeruginosa (PA), and Escherichia coli (EC),both susceptible (S) and resistant (R) strains, were determined usingthe broth microdilution method. Anticancer activities (IC50) of the compounds against breast cancer cell lines (MCF-7, MDA-MB-231,and MDA-MB-468) were studied using the MTT assay. The cellular uptakeof the compounds into bacterial and cancer cells was also studiedvia confocal and fluorescence imaging. Noncancerous cells MRC-5 andMCF-10A were used to compare the selectivity of the compounds to bacterialor cancer cells. RuCOOH alone demonstrated MIC values of >128 μMagainst all eight bacteria, whereas its Arg-Trp conjugates showedlower MIC values (2–32 μM) against all bacteria exceptPA­(R) and AB­(S). A significant 4-fold reduction in MIC values (from>128 to 2–32 μM) was observed when the conjugatesweretested against EC­(S) and AB­(R) compared to RuCOOH alone. For anticanceractivities, RuCOOH alone demonstrated IC50 values of >100μM, whereas its Arg-Trp conjugates (RuRW6, RuRW8, and RuRW9)showed lower IC50 values (5.44–93.08 μM) againstall three breast cancer cell lines. Cellular uptake studies demonstratedthe associations of RuRW9 with bacteria and breast cancer cells, wherebya red color signal was observed in the areas presented with cellswhen compared to the control and RuCOOH alone. MTT assay presentedthat all conjugates are selective in terms of selective index (SI)values toward EC bacteria instead of MRC-5 and the MDA-MB-468 breastcancer cell line instead of MCF-10A. Arg-Trp peptides enhanced theantibacterial and anticancer activities of the Ru­(PS), which highlightedthe pertinence of combining the use of photosensitizers and targetingagents to fight against multidrug-resistant bacteria and breast cancer.

Although photodynamic therapy (PDT) has been used successfully to treat an assortment of different types of cancer, it has yet to reach the level of mainstream medicine on either side of the Atlantic. Unsubstantiated claims of PDT's efficacy in the past may be part of the reason for this. However, perhaps the main obstacle to PDT's endorsement by conventional medicine is the limited number of high-quality randomized controlled trials (RCTs) comparing it with relevant comparators for all meaningful outcomes, including effectiveness, safety, adverse events, quality of life, survival, and cost. Based on a Health Technology Assessment report on the current status of PDT and consultation with professional groups, specialist societies, and clinical study groups in the United Kingdom, this article explores the current clinical guidelines for use of PDT in cancer treatment and the dearth of supportive data from RCTs.