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      HPMA-Based Copolymers Carrying STAT3 Inhibitor Cucurbitacin-D as Stimulus-Sensitive Nanomedicines for Oncotherapy

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          Abstract

          The study describes the synthesis, physicochemical properties, and biological evaluation of polymer therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers intended for a tumor-targeted immuno-oncotherapy. Water-soluble linear and cholesterol-containing HPMA precursors were synthesized using controlled reversible addition–fragmentation chain transfer polymerization to reach molecular weight M n about 2 × 10 4 g·mol −1 and low dispersity. These linear or self-assembled micellar conjugates, containing immunomodulatory agent cucurbitacin-D (CuD) or the anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond, showed a hydrodynamic size of 10–30 nm in aqueous solutions. The CuD-containing conjugates were stable in conditions mimicking blood. Importantly, a massive release of active CuD in buffer mimicking the acidic tumor environment was observed. In vitro, both the linear (LP-CuD) and the micellar (MP-CuD) conjugates carrying CuD showed cytostatic/cytotoxic activity against several cancer cell lines. In a murine metastatic and difficult-to-treat 4T1 mammary carcinoma, only LP-CuD showed an anticancer effect. Indeed, the co-treatment with Dox-containing micellar polymer conjugate and LP-CuD showed potentiation of the anticancer effect. The results indicate that the binding of CuD, characterized by prominent hydrophobic nature and low bioavailability, to the polymer carrier allows a safe and effective delivery. Therefore, the conjugate could serve as a potential component of immuno-oncotherapy schemes within the next preclinical evaluation.

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          Most cited references54

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            A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

            We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                28 January 2021
                February 2021
                : 13
                : 2
                : 179
                Affiliations
                [1 ]Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského náměstí 2, CZ-162 06 Prague 6, Czech Republic; tavares@ 123456imc.cas.cz (M.R.T.); konefal@ 123456imc.cas.cz (R.K.); etrych@ 123456imc.cas.cz (T.E.)
                [2 ]Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic; klara.hrabankova@ 123456biomed.cas.cz (K.H.); martin.kana@ 123456biomed.cas.cz (M.K.); rihova@ 123456biomed.cas.cz (B.Ř.); sirova@ 123456biomed.cas.cz (M.Š.)
                Author notes
                [* ]Correspondence: chytil@ 123456imc.cas.cz ; Tel.: +420-296-809-230
                Author information
                https://orcid.org/0000-0001-5908-5182
                https://orcid.org/0000-0002-7135-9796
                Article
                pharmaceutics-13-00179
                10.3390/pharmaceutics13020179
                7911143
                33525658
                3c9d7e3b-ecbe-4084-9470-80bba1e2d845
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 December 2020
                : 23 January 2021
                Categories
                Article

                cucurbitacin-d,immuno-oncotherapy,n-(2-hydroxypropyl) methacrylamide (hpma),ph-controlled release,signal transducer and activator of transcription 3 (stat3) inhibition

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