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      Doxorubicin Loaded Poloxamer Thermosensitive Hydrogels: Chemical, Pharmacological and Biological Evaluation

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          Abstract

          (1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several characterizations need to be optimized to better understand how hydrogel assisted chemotherapy works. Poloxamer 407 (P407) hydrogels were mixed with doxorubicin and physico-chemical, biological, and pharmacological characterizations were considered. (2) Methods: hydrogels were prepared by mixing P407 in PBS at 4 °C. Doxorubicin was added upon solutions became clear. Time-to-gelation, hydrogel morphology, and micelles were studied first. The effects of P407-doxorubicin were evaluated on MC-38 colon cancer cells. Furthermore, doxorubicin release was assessed and contrasted with non-invasive in vivo whole body fluorescence imaging. (3) Results: 25% P407 had favorable gelation properties with pore sizes of 30–180 µm. P407 micelles were approximately 5 nm in size. Doxorubicin was fully released in vitro from 25% P407 hydrogel within 120 h. Furthermore, P407 micelles strongly enhanced the anti-neoplastic effects of doxorubicin on MC-38 cells. In vivo fluorescence imaging revealed that hydrogels retained fluorescence signals at the injection site for 168 h. (4) Conclusions: non-invasive imaging showed how P407 gels retained drug at the injection site. Doxorubicin P407 micelles strongly enhanced the anti-tumor effects.

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          Most cited references47

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          Acidic extracellular microenvironment and cancer

          Acidic extracellular pH is a major feature of tumor tissue, extracellular acidification being primarily considered to be due to lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-lactate co-transporter, monocarboxylate transporters, and the proton pump (H+-ATPase); these may also be associated with tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from hypoxia. In addition to lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in tumor progression is reviewed.
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            Novel injectable neutral solutions of chitosan form biodegradable gels in situ.

            A novel approach to provide, thermally sensitive neutral solutions based on chitosan/polyol salt combinations is described. These formulations possess a physiological pH and can be held liquid below room temperature for encapsulating living cells and therapeutic proteins; they form monolithic gels at body temperature. When injected in vivo the liquid formulations turn into gel implants in situ. This system was used successfully to deliver biologically active growth factors in vivo as well as an encapsulating matrix for living chondrocytes for tissue engineering applications. This study reports for the first time the use of polymer/polyol salt aqueous solutions as gelling systems, suggesting the discovery of a prototype for a new family of thermosetting gels highly compatible with biological compounds.
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              An overview of doxorubicin formulations in cancer therapy.

              The burden of cancer is continuously increasing, and is rapidly becoming a global pandemic. The first liposomal encapsulated anticancer drug which received clinical approval against malignancies including solid tumours, transplantable leukemias and lymphomas was Doxorubicin HCl. This review is aimed at providing an overview of doxorubicin in cancer therapy. Pegylated liposomal doxorubicin has a polyethylene glycol (PEG) layer around doxorubicin-containing liposome as the result of a process known as pegylation. Non-pegylated liposomal doxorubicin (NPLD) was developed to overcome the drawbacks associated with previous formulations. Nudoxa; (NPLD) with its unique drug delivery system offers the benefit of pegylated liposomal doxorubicin without hand foot syndrome as the major side effect. Future studies will be directed towards estimating the costs of treatment with the novel liposomal doxorubicin formulations in order to assess their widespread use and robustness in treating patients with cancer.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                08 May 2020
                May 2020
                : 25
                : 9
                : 2219
                Affiliations
                [1 ]Department of Radiology, Division Translational Nanobiomaterials and Imaging, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; c.k.chung@ 123456lumc.nl (C.K.C.); jgcouce@ 123456gmail.com (J.G.-C.); y.campos.mora@ 123456gmail.com (Y.C.); alanchan@ 123456clara.net (A.C.)
                [2 ]JeNaCell GmbH, Winzerlaer Straße 2, 07745 Jena, Germany; kralisch@ 123456jenacell.de
                [3 ]Department of Polymeric Biomaterials, Biomaterials Center (BIOMAT), University of Havana, San Lázaro y L. Municipio, Havana 10400, Cuba
                [4 ]Department of Ceramic and Metallic Biomaterials, Biomaterials Center (BIOMAT), University of Havana, San Lázaro y L. Municipio, Havana 10400, Cuba
                [5 ]Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; katja@ 123456bierau.net
                [6 ]Percuros B.V., Zernikedreef 8, 2333 CL Leiden, The Netherlands
                [7 ]Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; F.A.Ossendorp@ 123456lumc.nl
                Author notes
                [* ]Correspondence: l.j.cruz_ricondo@ 123456lumc.nl ; Tel.: +31-715-265-764
                Author information
                https://orcid.org/0000-0002-1105-3891
                Article
                molecules-25-02219
                10.3390/molecules25092219
                7248767
                32397328
                5448d17e-a508-4be7-bedf-0088861e343a
                © 2020 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
                : 07 April 2020
                : 07 May 2020
                Categories
                Article

                chemotherapy,doxorubicin,fluorescence imaging,poloxamer,sustained release,thermosensitive hydrogel

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