Cytotoxic Effects of Doxorubicin on Cancer Cells and Macrophages Depend Differently on the Microcarrier Structure.

Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment contains different infiltrating cells, including immune cells, which can affect the efficacy of antitumor drugs. Here, prototype microparticle-based systems for the delivery of the antitumor drug doxorubicin (DOX) were developed, and their cytotoxic effects on human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells were compared in vitro. DOX-containing calcium carbonate microparticles with or without a protective polyelectrolyte shell and polyelectrolyte microcapsules of about 2.4-2.5 µm in size were obtained through coprecipitation and spontaneous loading. All the microstructures exhibited a prolonged release of DOX. An estimation of the cytotoxicity of the DOX-containing microstructures showed that the encapsulation of DOX decreased its toxicity to macrophages and delayed the cytotoxic effect against tumor cells. The DOX-containing calcium carbonate microparticles with a protective polyelectrolyte shell were more toxic to the cancer cells than DOX-containing polyelectrolyte microcapsules, whereas, for the macrophages, the microcapsules were most toxic. It is concluded that DOX-containing core/shell microparticles with an eight-layer polyelectrolyte shell are optimal drug microcarriers due to their low toxicity to immune cells, even upon prolonged incubation, and strong delayed cytotoxicity against tumor cells.

Impact of Macrophages on the Interaction of Cetuximab-Functionalized Polyelectrolyte Capsules with EGFR-Expressing Cancer Cells.

Polyelectrolyte capsules (PCs) are a promising tool for anticancer drug delivery and tumor targeting. Surface functionalization of PCs with antibodies is widely used for providing their specific interactions with cancer cells. The efficiency of PC-based targeted delivery systems can be affected by the cellular heterogeneity of the tumor, particularly by the presence of tumor-associated macrophages. We used human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells in either monoculture or coculture to analyze the targeting capacity and internalization efficiency of PCs with a mean size of 1.03 ± 0.11 µm. The PCs were functionalized with the monoclonal antibody cetuximab targeting the human epidermal growth factor receptor (EGFR). We have shown that surface functionalization of the PCs with cetuximab ensures a specific interaction with EGFR-expressing cancer cells and promotes capsule internalization. In monoculture, the macrophages derived from human leukemia monocytic cells have been found to internalize both nonfunctionalized PCs and cetuximab-functionalized PCs (Cet-PCs) more intensely compared to epidermoid carcinoma cells. The internalization of Cet-PCs by cancer cells is mediated by lipid rafts of the cell membrane, whereas the PC internalization by macrophages is only slightly influenced by lipid rafts. Experiments with a coculture of human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells have shown that Cet-PCs preferentially interact with cancer cells, which are subsequently attacked by macrophages. These data can be used to further improve the strategy of PC functionalization for targeted delivery, with the cellular heterogeneity of the tumor microenvironment taken into consideration.

Designing Functionalized Polyelectrolyte Microcapsules for Cancer Treatment.

The engineering of delivery systems for drugs and contrasting labels ensuring the simultaneous imaging and treatment of malignant tumors is an important hurdle in developing new tools for cancer therapy and diagnosis. Polyelectrolyte microcapsules (MCs), formed by nanosized interpolymer complexes, represent a promising platform for the designing of multipurpose agents, functionalized with various components, including high- and low-molecular-weight substances, metal nanoparticles, and organic fluorescent dyes. Here, we have developed size-homogenous MCs with different structures (core/shell and shell types) and microbeads containing doxorubicin (DOX) as a model anticancer drug, and fluorescent semiconductor nanocrystals (quantum dots, QDs) as fluorescent nanolabels. In this study, we suggest approaches to the encapsulation of DOX at different stages of the MC synthesis and describe the optimal conditions for the optical encoding of MCs with water-soluble QDs. The results of primary characterization of the designed microcarriers, including particle analysis, the efficacy of DOX and QDs encapsulation, and the drug release kinetics are reported. The polyelectrolyte MCs developed here ensure a modified (prolonged) release of DOX, under conditions close to normal and tumor tissues; they possess a bright fluorescence that paves the way to their exploitation for the delivery of antitumor drugs and fluorescence imaging.