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Smart Polymers for Biomedical Applications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 55613

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Prof. Dr. Mitsuhiro Ebara

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Research Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba 305-0044, Japan
Interests: smart polymers; anti-inflammation; apoptosis; material symbiosis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

There has been a renewal of interest in controlling the “nano” structures/functions of biomolecules, and a considerable number of studies have been conducted on designing novel materials to meet these applications. Some special types of polymers, for example, have emerged as a very useful class of polymers and have their own special chemical properties and applications in various areas. These polymers are called “smart” polymers. Smart polymers have been extensively studied for more than 30 years. The characteristic feature that actually makes them smart is their ability to respond to very slight changes in the surrounding environment, such as temperature, pH, light, or certain chemicals. The uniqueness of these materials lies, not only in the fast macroscopic changes occurring in their structure, but also in these transitions being reversible. The responses are manifested as changes in one or more of the following: Shape, surface characteristics, solubility, formation of an intricate molecular assembly, sol-to-gel transition, and others. This Special Issue focuses on how to design smart polymers and how to apply them to biomedical fields.

Dr. Mitsuhiro Ebara
Guest Editor

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Keywords

Temperature-responsive polymers
pH-responsive polymers
Photo-responsive polymers
Shape-memory polymers
Nanofibers
Bioconjugates
Diagnosis
Cancer therapy
Mechanobiology
Anti-inflammatory therapy

Published Papers (10 papers)

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Research

12 pages, 1910 KiB

Open AccessArticle

Glycopolymer Grafted Silica Gel as Chromatographic Packing Materials

by Gaoqi Ma, Xitao Luo, Xitong Sun, Weiyan Wang, Qinghui Shou, Xiangfeng Liang and Huizhou Liu

Int. J. Mol. Sci. 2019, 20(1), 10; https://doi.org/10.3390/ijms20010010 - 20 Dec 2018

Cited by 7 | Viewed by 3628

Abstract

The modification of the surface of silica gel to prepare hydrophilic chromatographic fillers has recently become a research interest. Most researchers have grafted natural sugar-containing polymers onto chromatographic surfaces. The disadvantage of this approach is that the packing structure is singular and the application scope is limited. In this paper, we explore the innovative technique of grafting a sugar-containing polymer, 2-gluconamidoethyl methacrylamide (GAEMA), onto the surface of silica gel by atom transfer radical polymerization (ATRP). The SiO₂-g-GAEMA with ATRP reaction time was characterized by Fourier infrared analysis, Thermogravimetric analysis (TGA), and elemental analysis. As the reaction time lengthened, the amount of GAEMA grafted on the surface of the silica gel gradually increased. The GAEMA is rich in amide bonds and hydroxyl groups and is a typical hydrophilic chromatography filler. Finally, SiO₂-g-GAEMA (reaction time = 24 h) was chosen as the stationary phase of the chromatographic packing and evaluated with four polar compounds (uracil, cytosine, guanosine, and cytidine). Compared with unmodified silica gel, modified silica gel produces sharper peaks and better separation efficiency. This novel packing material may have a potential for application with highly isomerized sugar mixtures. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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26 pages, 4400 KiB

Open AccessArticle

Hyaluronic Acid-Decorated Chitosan Nanoparticles for CD44-Targeted Delivery of Everolimus

by Enrica Chiesa, Rossella Dorati, Bice Conti, Tiziana Modena, Emanuela Cova, Federica Meloni and Ida Genta

Int. J. Mol. Sci. 2018, 19(8), 2310; https://doi.org/10.3390/ijms19082310 - 07 Aug 2018

Cited by 55 | Viewed by 5726

Abstract

Bronchiolitis obliterans syndrome (BOS), caused by lung allograft-derived mesenchymal cells’ abnormal proliferation and extracellular matrix deposition, is the main cause of lung allograft rejection. In this study, a mild one-step ionotropic gelation method was set up to nanoencapsulate the everolimus, a key molecule in allograft organ rejection prevention, into hyaluronic acid-decorated chitosan-based nanoparticles. Rationale was the selective delivery of everolimus into lung allograft-derived mesenchymal cells; these cells are characterized by the CD44-overexpressing feature, and hyaluronic acid has proven to be a natural selective CD44-targeting moiety. The optimal process conditions were established by a design of experiment approach (full factorial design) aiming at the control of the nanoparticle size (≤200 nm), minimizing the size polydispersity (PDI 0.171 ± 0.04), and at the negative ζ potential maximization (−30.9 mV). The everolimus was successfully loaded into hyaluronic acid-decorated chitosan-based nanoparticles (95.94 ± 13.68 μg/100 mg nanoparticles) and in vitro released in 24 h. The hyaluronic acid decoration on the nanoparticles provided targetability to CD44-overexpressing mesenchymal cells isolated from bronchoalveolar lavage of BOS-affected patients. The mesenchymal cells’ growth tests along with the nanoparticles uptake studies, at 37 °C and 4 °C, respectively, demonstrated a clear improvement of everolimus inhibitory activity when it is encapsulated in hyaluronic acid-decorated chitosan-based nanoparticles, ascribable to their active uptake mechanism. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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22 pages, 3548 KiB

Open AccessArticle

Intra-Articular Formulation of GE11-PLGA Conjugate-Based NPs for Dexamethasone Selective Targeting—In Vitro Evaluation

by Enrica Chiesa, Silvia Pisani, Barbara Colzani, Rossella Dorati, Bice Conti, Tiziana Modena, Kevin Braeckmans and Ida Genta

Int. J. Mol. Sci. 2018, 19(8), 2304; https://doi.org/10.3390/ijms19082304 - 06 Aug 2018

Cited by 19 | Viewed by 3695

Abstract

Selectively targeted nanoscale drug delivery systems have recently emerged as promising intravenously therapeutic option for most chronic joint diseases. Here, a newly synthetized dodecapeptide (GE11)-polylactide-co-glycolide (PLGA)-based conjugate was used to prepare smart nanoparticles (NPs) intended for intra-articular administration and for selectively targeting Epidermal Growth Factor Receptor (EGFR). GE11-PLGA conjugate-based NPs are specifically uptaken by EGFR-overexpressed fibroblast; such as synoviocytes; which are the primarily cellular component involved in the development of destructive joint inflammation. The selective uptake could help to tune drug effectiveness in joints and to decrease local and systemic side effects. Dexamethasone (DXM) is a glucorticoid drug commonly used in joint disease treatment for both systemic and local administration route. In the present research; DXM was efficiently loaded into GE11-PLGA conjugate-based NPs through an eco-friendly nanoprecipitation method set up for this purpose. DXM loaded GE11-PLGA conjugate-based NPs revealed satisfactory ex vivo cytocompatibility; with proper size (≤150 nm) and good dimensional stability in synovial fluid. Intra-articular formulation was developed embedding DXM loaded GE11-PLGA conjugate-based NPs into thermosetting chitosan-based hydrogel; forming a biocompatible composite hydrogel able to quickly turn from liquid state into gel state at physiological temperature; within 15 min. Moreover; the use of thermosetting chitosan-based hydrogel extends the local release of active agent; DXM. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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16 pages, 5652 KiB

Open AccessArticle

Tailored Biodegradable and Electroactive Poly(Hydroxybutyrate-Co-Hydroxyvalerate) Based Morphologies for Tissue Engineering Applications

by Luís Amaro, Daniela M. Correia, Teresa Marques-Almeida, Pedro M. Martins, Leyre Pérez, José L. Vilas, Gabriela Botelho, Senentxu Lanceros-Mendez and Clarisse Ribeiro

Int. J. Mol. Sci. 2018, 19(8), 2149; https://doi.org/10.3390/ijms19082149 - 24 Jul 2018

Cited by 26 | Viewed by 4040

Abstract

Polymer-based piezoelectric biomaterials have already proven their relevance for tissue engineering applications. Furthermore, the morphology of the scaffolds plays also an important role in cell proliferation and differentiation. The present work reports on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), a biocompatible, biodegradable, and piezoelectric biopolymer that has been processed in different morphologies, including films, fibers, microspheres, and 3D scaffolds. The corresponding magnetically active PHBV-based composites were also produced. The effect of the morphology on physico-chemical, thermal, magnetic, and mechanical properties of pristine and composite samples was evaluated, as well as their cytotoxicity. It was observed that the morphology does not strongly affect the properties of the pristine samples but the introduction of cobalt ferrites induces changes in the degree of crystallinity that could affect the applicability of prepared biomaterials. Young’s modulus is dependent of the morphology and also increases with the addition of cobalt ferrites. Both pristine and PHBV/cobalt ferrite composite samples are not cytotoxic, indicating their suitability for tissue engineering applications. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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15 pages, 4577 KiB

Open AccessArticle

LAT1-Targeting Thermoresponsive Fluorescent Polymer Probes for Cancer Cell Imaging

by Minami Matsuura, Mariko Ohshima, Yuki Hiruta, Tomohiro Nishimura, Kenichi Nagase and Hideko Kanazawa

Int. J. Mol. Sci. 2018, 19(6), 1646; https://doi.org/10.3390/ijms19061646 - 01 Jun 2018

Cited by 34 | Viewed by 5966

Abstract

L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) were synthesized and their affinity for LAT1 was evaluated. The synthesized polymer probes interacted with LAT1 on HeLa cells, and inhibition of l-[³H]-leucine, one of the substrates for LAT1 uptake, was investigated. l-Tyrosine-conjugated P(NIPAAm-co-DMAAm) inhibited the uptake of l-[³H]-leucine, while P(NIPAAm-co-DMAAm) and l-phenylalanine-conjugated P(NIPAAm-co-DMAAm) did not. This result indicated that l-tyrosine-conjugated polymer has a high affinity for LAT1. The fluorescent polymer probes were prepared by modification of a terminal polymer group with fluorescein-5-maleimide (FL). Above the polymer transition temperature, cellular uptake of the polymer probes was observed because the polymers became hydrophobic, which enhanced the interaction with the cell membrane. Furthermore, quantitative analysis of the fluorescent probe using flow cytometry indicated that l-tyrosine-conjugated P(NIPAAm-co-DMAAm)-FL shows higher fluorescence intensity earlier than P(NIPAAm-co-DMAAm)-FL. The result suggested that cellular uptake was promoted by the LAT1 affinity site. The developed LAT1-targeting thermoresponsive fluorescent polymer probes are expected to be useful for cancer cell imaging. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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13 pages, 5249 KiB

Open AccessArticle

Preparation of Biodegradable Oligo(lactide)s-Grafted Dextran Nanogels for Efficient Drug Delivery by Controlling Intracellular Traffic

by Yuichi Ohya, Akihiro Takahashi and Akinori Kuzuya

Int. J. Mol. Sci. 2018, 19(6), 1606; https://doi.org/10.3390/ijms19061606 - 30 May 2018

Cited by 9 | Viewed by 5374

Abstract

Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex-g-SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex-g-SS-OLA with attached Gal residues and tetraethylenepentamine (EI₄) groups, EI₄/Gal-Dex-g-SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI₄/Gal-Dex-g-SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI₄/Gal-Dex-g-SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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15 pages, 2818 KiB

Open AccessArticle

Effect of Temperature Changes on Serum Protein Adsorption on Thermoresponsive Cell-Culture Surfaces Monitored by A Quartz Crystal Microbalance with Dissipation

by Jun Kobayashi, Yoshinori Arisaka, Nobuhiko Yui, Yoshikatsu Akiyama, Masayuki Yamato and Teruo Okano

Int. J. Mol. Sci. 2018, 19(5), 1516; https://doi.org/10.3390/ijms19051516 - 18 May 2018

Cited by 20 | Viewed by 5993

Abstract

Thermoresponsive cell-culture polystyrene (PS) surfaces that are grafted with poly(N-isopropylacrylamide) (PIPAAm) facilitate the cultivation of cells at 37 °C and the detachment of cultured cells as a sheet with an underlying extracellular matrix (ECM) by reducing the temperature. However, the ECM and cell detachment mechanisms are still unclear because the detachment of cells from thermoresponsive surfaces is governed by complex interactions among the cells/ECM/surface. To explore the dynamic behavior of serum protein adsorption/desorption, thermoresponsive surfaces that correspond to thermoresponsive tissue-culture PS dishes were formed on sensor chips for quartz crystal microbalance with dissipation (QCM-D) measurements. X-ray photoelectron spectroscopy (XPS) measurements and temperature-dependent frequency and dissipation shifts, Δf and ΔD, using QCM-D revealed that the thermoresponsive polymers were successfully grafted onto oxidized, thin PS films on the surfaces of the sensor chips. Increased amounts of adsorbed bovine serum albumin (BSA) and fibronectin (FN) were observed on the thermoresponsive polymer-grafted surfaces at 37 °C when compared with those at 20 °C because of enhanced hydrophobic interactions with the hydrophobic, thermoresponsive surface. While the calculated masses of adsorbed BSA and FN using QCM-D were 3–5 times more than those that were obtained from radiolabeling, the values were utilized for relative comparisons among the same substrate. More importantly, the thermoresponsive, dynamic behavior of serum protein adsorption/desorption was monitored using the QCM-D technique. Observations of this dynamic behavior revealed that the BSA and FN that were adsorbed at 37 °C remained on both surfaces after decreasing the temperature to 20 °C. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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17 pages, 4981 KiB

Open AccessArticle

Thermosensitive Injectable Hydrogel for Simultaneous Intraperitoneal Delivery of Doxorubicin and Prevention of Peritoneal Adhesion

by Chih-Hao Chen, Chang-Yi Kuo, Shih-Hsien Chen, Shih-Hsuan Mao, Chih-Yen Chang, K. T. Shalumon and Jyh-Ping Chen

Int. J. Mol. Sci. 2018, 19(5), 1373; https://doi.org/10.3390/ijms19051373 - 04 May 2018

Cited by 38 | Viewed by 7052

Abstract

To improve intraperitoneal chemotherapy and to prevent postsurgical peritoneal adhesion, we aimed to develop a drug delivery strategy for controlled release of a chemotherapeutic drug from the intraperitoneally injected thermosensitive poly(N-isopropylacrylamide)-based hydrogel (HACPN), which is also endowed with peritoneal anti-adhesion properties. Anticancer drug doxorubicin (DOX) was loaded into the hydrogel (HACPN-DOX) to investigate the chemotherapeutic and adhesion barrier effects in vivo. A burst release followed by sustained release of DOX from HACPN-DOX was found due to gradual degradation of the hydrogel. Cell culture studies demonstrated the cytotoxicity of released DOX toward CT-26 mouse colon carcinoma cells in vitro. Using peritoneal carcinomatosis animal model in BALB/c mice with intraperitoneally injected CT-26 cells, animals treated with HACPN-DOX revealed the best antitumor efficacy judging from tumor weight and volume, survival rate, and bioluminescence signal intensity when compared with treatment with free DOX at the same drug dosage. HACPN (or HACPN-DOX) also significantly reduced the risk of postoperative peritoneal adhesion, which was generated by sidewall defect-cecum abrasion in tumor-bearing BALB/c mice, from gross and histology analyses. This study could create a paradigm to combine controlled drug release with barrier function in a single drug-loaded injectable hydrogel to enhance the intraperitoneal chemotherapeutic efficacy while simultaneously preventing postsurgical adhesion. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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10 pages, 515 KiB

Open AccessArticle

Mesenchylmal Stem Cell Culture on Poly(N-isopropylacrylamide) Hydrogel with Repeated Thermo-Stimulation

by Aya Mizutani Akimoto, Erika Hasuike Niitsu, Kenichi Nagase, Teruo Okano, Hideko Kanazawa and Ryo Yoshida

Int. J. Mol. Sci. 2018, 19(4), 1253; https://doi.org/10.3390/ijms19041253 - 21 Apr 2018

Cited by 23 | Viewed by 5512

Abstract

We prepared thermoresponsive hydrogels by mixing poly(N-isopropylacrylamide) (PNIPAAm) derivatives as the main chain components, octa-arm polyethylene glycol (PEG) as a crosslinker, and the Arg-Gly-Asp-Ser (RGDS) peptides as cell adhesion units. Human bone marrow-derived mesenchymal stem cells (hbmMSCs) were cultured on the hydrogels. The PNIPAAm gel prepared by the post-crosslinking gelation method was revealed to be cytocompatible and showed temperature-dependent changes in mechanical properties. Repeated changes in the swelling ratio of the PNIPAAm gel affected the shape of the hbmMSCs. With respect to both cytocompatibility and reversibility of changes in mechanical properties, the PNIPAAm gel system could be potentially useful for the analysis of cell mechanobiology. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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15 pages, 35521 KiB

Open AccessArticle

A Lipophilic IR-780 Dye-Encapsulated Zwitterionic Polymer-Lipid Micellar Nanoparticle for Enhanced Photothermal Therapy and NIR-Based Fluorescence Imaging in a Cervical Tumor Mouse Model

by Santhosh Kalash Rajendrakumar, Ning-Chu Chang, Adityanarayan Mohapatra, Saji Uthaman, Byeong-Il Lee, Wei-bor Tsai and In-Kyu Park

Int. J. Mol. Sci. 2018, 19(4), 1189; https://doi.org/10.3390/ijms19041189 - 13 Apr 2018

Cited by 25 | Viewed by 7921

Abstract

To prolong blood circulation and avoid the triggering of immune responses, nanoparticles in the bloodstream require conjugation with polyethylene glycol (PEG). However, PEGylation hinders the interaction between the nanoparticles and the tumor cells and therefore limits the applications of PEGylated nanoparticles for therapeutic drug delivery. To overcome this limitation, zwitterionic materials can be used to enhance the systemic blood circulation and tumor-specific delivery of hydrophobic agents such as IR-780 iodide dye for photothermal therapy. Herein, we developed micellar nanoparticles using the amphiphilic homopolymer poly(12-(methacryloyloxy)dodecyl phosphorylcholine) (PCB-lipid) synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. The PCB-lipid can self-assemble into micelles and encapsulate IR-780 dye (PCB-lipid–IR-780). Our results demonstrated that PCB-lipid–IR-780 nanoparticle (NP) exhibited low cytotoxicity and remarkable photothermal cytotoxicity to cervical cancer cells (TC-1) upon near-infrared (NIR) laser irradiation. The biodistribution of PCB-lipid–IR-780 showed higher accumulation of PCB-lipid–IR-780 than that of free IR-780 in the TC-1 tumor. Furthermore, following NIR laser irradiation of the tumor region, the PCB-lipid–IR-780 accumulated in the tumor facilitated enhanced tumor ablation and subsequent tumor regression in the TC-1 xenograft model. Hence, these zwitterionic polymer-lipid hybrid micellar nanoparticles show great potential for cancer theranostics and might be beneficial for clinical applications. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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