Simulation of mass transport during intraperitoneal chemotherapy : a parametrical model of single tumor nodules

OBJECTIVES Patients with peritoneal carcinomatosis suffer from a widespread metastatic growth of tumor nodules in the peritoneal cavity. Although Intraperitoneal (IP) chemotherapy allows for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration, actual application of IP chemotherapy is limited due to poor drug penetration (typically a few millimeters) in the tumor tissue. It is thus essential to better understand the drug transport during IP chemotherapy. METHODS A 3D computational fluid dynamics model of a tumor nodule with necrotic core was created in Comsol® (COMSOL, Inc., Burlington, USA) describing the drug transport occurring during IP chemotherapy, including convective/diffusive/reactive drug transport in two tumor geometries (a spherical baseline model with radius rsphere,large=1 cm/rsphere,small=2 mm and rnecrotic,large=5 mm/rnecrotic,large=1 mm). To assess the efficiency of drug administration, a penetration depth (PD) was defined as the percentage of the total radius in which the drug concentration resulted to be over 6.6E-3 mol/m3. These baseline models were subsequently adapted to evaluate the effect of therapy-related parameters (different drugs, vascular properties etc.) on drug penetration. RESULTS A large differences in PD (PD; % of total radius) were found in the baseline cases for the two different scales (PDsphere,large= 4.04%; PDsphere,small=20.82%).Vascular normalization therapy yielded different outcomes (ΔPDsphere,large+2.95%; ΔPDsphere,small +17.95%). Both cases showed less penetration when paclitaxel was used as opposed to cisplatin. This effect was more pronounced in the smaller geometry (ΔPDsphere,large =-1.91%; ΔPDsphere,small =-10.25%). CONCLUSIONS The model is able to predict drug penetration depth for different sets of IP chemotherapy-related parameters, which may lead to optimization of drug transport during IP chemotherapy

Intraperitoneal chemotherapy for peritoneal metastases : an expert opinion

Introduction: The rationale for intraperitoneal (IP) drug delivery for patients with peritoneal metastases (PM) is based on the pharmacokinetic advantage resulting from the peritoneal-plasma barrier, and on the potential to adequately treat small, poorly vascularized PM. Despite a history of more than three decades, many aspects of IP drug delivery remain poorly studied. Areas covered: We outline the anatomy and physiology of the peritoneal cavity, including the pharmacokinetics of IP drug delivery. We discuss transport mechanisms governing tissue penetration of IP chemotherapy, and how these are affected by the biomechanical properties of the tumor stroma. We provide an overview of the current clinical evidence on IP chemotherapy in ovarian, colorectal, and gastric cancer. We discuss the current limitations of IP drug delivery and propose several potential areas of progress. Expert opinion: The potential of IP drug delivery is hampered by off-label use of drugs developed for systemic therapy. The efficacy of IP chemotherapy for PM depends on cancer type, disease extent, and mode of drug delivery. Results from ongoing randomized trials will allow to better delineate the potential of IP chemotherapy. Promising approaches include IP aerosol therapy, prolonged delivery platforms such as gels or biomaterials, and the use of nanomedicine

Peroxiredoxin III : a candidate for drug resistance to chemotherapy : a thesis presented in partial fulfillment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Palmerston North, New Zealand

The development of drug resistance to chemotherapeutic drugs is a serious obstacle in the successful treatment of cancer. New cancer drugs are continually being developed with the goal of increasing the effectiveness of chemotherapy. However, new mechanisms of drug resistance are also continually being identified. Understanding the mechanisms of drug resistance is a vital step in identifying new drug targets which may prevent or reduce the development of drug resistance. A recent unpublished study identified peroxiredoxin III (prx III) as being up-regulated in breast cancer cells in culture following exposure to the commonly used anti-cancer drug doxorubicin. Doxorubicin and the almost identical drug epirubicin have multiple mechanisms of activity. One function of these drugs is to increase intracellular hydrogen peroxide (H 2 O 2 ) concentrations to induce cell death. As prx III is a mitochondrial protein which reduces H 2 O 2 , it has been suggested that increased expression of prx III may contribute to the development of drug resistance to doxorubicin or epirubicin. However, before such a role for prx III in the development of drug resistance can be further investigated, prx III expression needs to be examined in patients undergoing chemotherapy. The aim of this study was to examine prx III expression in the white blood cells of patients undergoing chemotherapy with epirubicin, and in healthy control subjects. Additionally, as the activity of a number of peroxiredoxins has been shown to be modulated through the formation of complexes and over-oxidation, complex formation and over-oxidation in response to treatment with doxorubicin or epirubicin was also examined. The results of this study could identify a new target for preventing or reducing the development of drug resistance. While the sample sizes were too small to draw conclusions, some patients showed a change in the expression of peroxiredoxin III following chemotherapy with epirubicin, suggesting that further investigation into the expression of peroxiredoxin III following chemotherapy would be worthwhile

Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice.

Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (MAT1A) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of MAT1A in individuals who received chemotherapy. Overexpression of MAT1A in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting MAT1A upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy

Modeling Three-dimensional Invasive Solid Tumor Growth in Heterogeneous Microenvironment under Chemotherapy

A systematic understanding of the evolution and growth dynamics of invasive solid tumors in response to different chemotherapy strategies is crucial for the development of individually optimized oncotherapy. Here, we develop a hybrid three-dimensional (3D) computational model that integrates pharmacokinetic model, continuum diffusion-reaction model and discrete cell automaton model to investigate 3D invasive solid tumor growth in heterogeneous microenvironment under chemotherapy. Specifically, we consider the effects of heterogeneous environment on drug diffusion, tumor growth, invasion and the drug-tumor interaction on individual cell level. We employ the hybrid model to investigate the evolution and growth dynamics of avascular invasive solid tumors under different chemotherapy strategies. Our simulations reproduce the well-established observation that constant dosing is generally more effective in suppressing primary tumor growth than periodic dosing, due to the resulting continuous high drug concentration. In highly heterogeneous microenvironment, the malignancy of the tumor is significantly enhanced, leading to inefficiency of chemotherapies. The effects of geometrically-confined microenvironment and non-uniform drug dosing are also investigated. Our computational model, when supplemented with sufficient clinical data, could eventually lead to the development of efficient in silico tools for prognosis and treatment strategy optimization.Comment: 41 pages, 8 figure

Aerosolization of nanotherapeutics as a newly emerging treatment regimen for peritoneal carcinomatosis

Recent advances in locoregional chemotherapy have opened the door to new approaches for the clinical management of peritoneal carcinomatosis (PC) by facilitating the delivery of anti-neoplastic agents directly to the tumor site, while mitigating adverse effects typically associated with systemic administration. In particular, an innovative intra-abdominal chemotherapeutic approach, known as Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), was recently introduced to the intraperitoneal (IP) therapy regimens as a palliative therapeutic option in patients with PC, presumably providing a better drug distribution pattern together with deeper drug penetration into tumor nodules within the peritoneal space. Furthermore, the progress of nanotechnology in the past few decades has prompted the application of different nanomaterials in IP cancer therapy, offering new possibilities in this field ranging from an extended retention time to sustained drug release in the peritoneal cavity. This review highlights the progress, challenges, and opportunities in utilizing cancer nanotherapeutics for locoregional drug delivery, with a special emphasis on the aerosolization approach for intraperitoneal therapies