Penetration Efficiency of Antitumor Agents in Ovarian Cancer Spheroids: The Case of Recombinant Targeted Toxin DARPin-LoPE and the Chemotherapy Drug, Doxorubicin

Abstract

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.

Antimicrobial Peptides as New Combination Agents in Cancer Therapeutics: A Promising Protocol against HT-29 Tumoral Spheroids

“…When selecting the drugs, we also considered their molecular size. Previous studies have shown that using two anticancer compounds with different molecular weights reduces the penetration efficiency of the high molecular weight agents [56]. In our case, by using the two compounds, both with low molecular weights, we showed that either separate or combination treatments are efficient against the spheroids.…”

UCNP-based Photoluminescent Nanomedicines for Targeted Imaging and Theranostics of Cancer

“…In this study, we obtained a new type of theranostic nanocomplexes based on UCNP coated with PEG and functionalized with the recombinant targeted toxin DARPin-LoPE [ 40 , 42 ]. Selective binding of UCNP-DARPin-LoPE nanocomplexes to HER2-overexpressing human breast adenocarcinoma cells was shown.…”

“…Selective binding of UCNP-DARPin-LoPE nanocomplexes to HER2-overexpressing human breast adenocarcinoma cells was shown. Besides, a significant decrease in cancer cell viability was revealed due to the selective action of the targeted toxin DARPin-LoPE by blocking protein biosynthesis [ 42 ] (see also Figure S3 ). The demonstrated ability of the obtained nanocomplexes to visualize tumors indicates their potential as agents for bioimaging.…”

“…Recently created targeted toxin DARPin-LoPE [ 41 ] consists of a HER2-specific DARPin and a low immunogenic LoPE and can act as a targeting and toxic module in nanocomplexes. DARPin-LoPE exhibits high activity against HER2-overexpressing cancer cells both in vitro and in vivo by inducing apoptosis [ 40 , 42 ]. It was also shown that DARPin-LoPE effectively inhibits the growth of HER2-expressing human ovarian carcinoma xenografts and exhibits low immunogenicity and general toxicity which limit the use of PE-based toxins: less pronounced side effects, specifically vascular leak syndrome, liver and kidney tissue degradation [ 42 ].…”

“…DARPin-LoPE exhibits high activity against HER2-overexpressing cancer cells both in vitro and in vivo by inducing apoptosis [ 40 , 42 ]. It was also shown that DARPin-LoPE effectively inhibits the growth of HER2-expressing human ovarian carcinoma xenografts and exhibits low immunogenicity and general toxicity which limit the use of PE-based toxins: less pronounced side effects, specifically vascular leak syndrome, liver and kidney tissue degradation [ 42 ]. It also leads to formation of the lower antibody titer following the treatment course, and rapid decline in concentration of specific antibodies.…”