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 Mn about 2 × 104 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.
Highlights
Conventional cancer chemotherapy often brings unsatisfactory results and/or significant toxicity; new treatment alternatives to defeat cancer are demanded [1,2].There is strong evidence documented in the literature to support the application of immunotherapeutic protocols for the treatment of cancer including reactivation of the immune system against cancer cells to suppress the tumor growth
We present the design, synthesis, and physicochemical and biological evaluation of the HPMA copolymer conjugates with signal transducer and activator of transcription 3 (STAT3) inhibitor CuD bound to the polymer via the pH-sensitive spacer designed for an effective tumor-targeting drug delivery and immuno-oncotherapy by a blockade of STAT3 signaling pathway in tumor cells
Our previous studies [35,37,38] on micelle-forming amphiphilic HPMA copolymers with cholesterol derivatives showed polymer carriers with the mentioned molecular weight (Mw) as suitable micellar drug carriers; the previous conditions used for their synthesis were applied in this study
Summary
Conventional cancer chemotherapy often brings unsatisfactory results and/or significant toxicity; new treatment alternatives to defeat cancer are demanded [1,2]. When compared to smaller molecules, biomaterials with increased hydrodynamic size can accumulate in the tumor tissue at a higher extent [24] and those bigger than 10 nm, exceeding the renal filtration limit, can reach circulation several times longer than free parent drugs [25] This effect contributes to the improvement of pharmacokinetic profile and therapeutic efficacy when compared to the conventional anticancer treatment with low-molecular-weight therapeutics [22,26,27]. There have been many studies describing the characteristics of polymer carriers based on N-(2-hydroxypropyl) methacrylamide (HPMA), which are water-soluble, biocompatible, nonimmunogenic, and nontoxic They are known to prolong the circulation time of the therapeutics, i.e., drugs and/or ligands, deliver them to their biological sites, i.e., tissues or receptors, increase the tumor accumulation, and reduce adverse effects of therapy. The combination of immunotherapy and oncotherapy should promote the immunomodulatory intervention by STAT3 inhibition, improving the outcome of the disease
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