Malignant tumors are characterized by structural and molecular peculiarities providing a possibility to directionally deliver antitumor drugs with minimal impact on healthy tissues and reduced side effects. Newly formed blood vessels in malignant lesions exhibit chaotic growth, disordered structure, irregular shape and diameter, protrusions, and blind ends, resulting in immature vasculature; the newly formed lymphatic vessels also have aberrant structure. Structural features of the tumor vasculature determine relatively easy penetration of large molecules as well as nanometer-sized particles through a blood–tissue barrier and their accumulation in a tumor tissue. Also, malignant cells have altered molecular profile due to significant changes in tumor cell metabolism at every level from the genome to metabolome. Recently, the tumor interaction with cells of immune system becomes the focus of particular attention, that among others findings resulted in extensive study of cells with preferential tropism to tumor. In this review we summarize the information on the diversity of currently existing approaches to targeted drug delivery to tumor, including (i) passive targeting based on the specific features of tumor vasculature, (ii) active targeting which implies a specific binding of the antitumor agent with its molecular target, and (iii) cell-mediated tumor targeting.
The efficiency of delivering a therapeutic agent into a tumor is among the crucial factors determining the prospects for its clinical use. This problem is particularly acute in the case of targeted antitumor agents since many of them are high-molecular-weight compounds. In this work, the penetration of therapeutic agents of two distinct molecular weights into the spheroids of ovarian adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) was studied. It was shown that the low-molecular-weight chemotherapy drug, doxorubicin (~0.5 kDa), effectively penetrates through almost the entire depth of a 300 to 400 μm spheroid, while the penetration depth of the HER2-specific recombinant targeted toxin, DARPin-LoPE (~42 kDa), is only a few surface layers of cells and does not exceed 70 μm. The low penetration of the targeted toxin into spheroid was shown along with a significant decrease in its efficiency against the three-dimensional tumor spheroid as compared with the two-dimensional monolayer culture. The approaches to increasing the accumulation of agents in the tumor are presented and prospects of their use in order to improve the effectiveness of therapy are discussed.
Tumor resistance to therapy is associated with the 3D organization and peculiarities of the tumor microenvironment, of which intercellular adhesion is a key participant. In this work, the abundance of contact proteins was compared in SKOV-3 and SKOV-3.ip human ovarian adenocarcinoma cell lines, cultivated in monolayers, tumor spheroids and collagen hydrogels. Three-dimensional models were characterized by extremely low expression of basic molecules of adherens junctions E-cadherin and demonstrated a simultaneous decrease in desmosomal protein desmoglein-2, gap junction protein connexin-43 and tight junction proteins occludin and ZO-1. The reduction in the level of contact proteins was most pronounced in collagen hydrogel, accompanied by significantly increased resistance to treatment with doxorubicin and targeted anticancer toxin DARPin-LoPE. Thus, we suggest that 3D models of ovarian cancer, especially matrix-based models, tend to recapitulate tumor microenvironment and treatment responsiveness to a greater extent than monolayer culture, so they can be used as a highly relevant platform for drug efficiency evaluation.
The development of targeted toxins based on non-immunoglobulin targeting
molecules appears to be one of the most advanced approaches in the targeted
therapy of malignant tumors with a high expression of the HER2 receptor.
Earlier, we showed that the targeted toxin DARPin-PE40 consisting of the
HER2-specific non-immunoglobulin polypeptide (the targeting module) and a
fragment of Pseudomonas exotoxin A (the toxic module) exhibits
an antitumor effect in vivo against the HER2-positive
adenocarcinoma xenograft. In this work, an in-depth analysis of the effect of
DARPin-PE40 on the growth dynamics of experimental xenograft tumors was carried
out. DARPin-PE40 was shown to inhibit tumor growth at a dose of 25 and 50
μg/animal and to cause tumor node reduction at a dose of 80
μg/animal, followed by growth resumption at the end of therapy. An
evaluation of the tumor growth dynamics revealed statistically significant
differences in tumor volume in mice in the experimental groups compared to the
control group. The results testify to the potential of using the created
targeted toxin as an agent for the targeted therapy of HER2-overexpressing
tumors.
Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal cells by change in the expression and metabolism profile and acquire the ability to invade. The cultivation conditions of cancer cells can provoke EMT, which in turn can affect their resistance to therapy. Therefore, when researching and developing anticancer drugs, it is important to take into account that the chosen research model can affect further results related to the resistance of tumor cells to antitumor agents. The aim of this work was to compare the expression profile of proteins representing the main types of intercellular contacts in human ovarian adenocarcinoma cells in a monolayer, tumor spheroids and collagen hydrogel.
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