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        Injectable hydrogels for delivering biotherapeutic molecules

        Mathew, Ansuja Pulickal,Uthaman, Saji,Cho, Ki-Hyun,Cho, Chong-Su,Park, In-Kyu Elsevier 2018 INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES Vol.110 No.-

        <P><B>Abstract</B></P> <P>To date, numerous delivery systems based on either organic or inorganic material have been developed to achieve efficient and sustained delivery of therapeutics. Hydrogels, which are three dimensional networks of crosslinked hydrophilic polymers, have a significant role in solving the clinical and pharmacological limitations of present systems because of their biocompatibility, ease of preparation and unique physical properties such as a tunable porous nature and affinity for biological fluids. Development of an <I>in situ</I> forming injectable hydrogel system has allowed excellent spatial and temporal control, unlike systemically administered therapeutics. Injectable hydrogel systems can offset difficulties with conventional hydrogel-based drug delivery systems in the clinic by forming a drug/gene delivery or cell-growing depot in the body with a single injection, thereby enabling patient compliance and comfort. Carbohydrate polymers are widely used for the synthesis of injectable <I>in situ</I>-forming hydrogels because of ready availability, presence of modifiable functional groups, biocompatibility and other physiochemical properties. In this review, we discuss different aspects of injectable hydrogels, such as bulk hydrogels/macrogels, microgels, and nanogels derived from natural polymers, and their importance in the delivery of therapeutics such as genes, drugs, cells or other biomolecules and how these revolutionary systems can complement existing therapeutic delivery systems.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

      • KCI등재

        Vimentin Targeted Nano-gene Carrier for Treatment of Renal Diseases

        Mathew Ansuja Pulickal,Uthaman Saji,Bae Eun Hui,Lee Jae Young,Park In-Kyu 대한의학회 2021 Journal of Korean medical science Vol.36 No.49

        Background: Chronic kidney disease (CKD) is a global health problem, and there is no permanent treatment for reversing kidney failure; thus, early diagnosis and effective treatment are required. Gene therapy has outstanding potential; however, the lack of safe gene delivery vectors, a reasonable transfection rate, and kidney targeting ability limit its application. Nanoparticles can offer innovative ways to diagnose and treat kidney diseases as they facilitate targetability and therapeutic efficacy. Methods: Herein, we developed a proximal renal tubule-targeting gene delivery system based on alternative copolymer (PS) of sorbitol and polyethyleneimine (PEI), modified with vimentin-specific chitobionic acid (CA), producing PS-conjugated CA (PSC) for targeting toward vimentin-expressing cells in the kidneys. In vitro studies were used to determine cell viability, transfection efficiency, serum influence, and specific uptake in the human proximal renal tubular epithelial cell line (HK-2). Finally, the targeting efficiency of the prepared PSC gene carriers was checked in a murine model of Alport syndrome. Results: Our results suggested that the prepared polyplex showed low cytotoxicity, enhanced transfection efficiency, specific uptake toward HK-2 cells, and excellent targeting efficiency toward the kidneys. Conclusion: Collectively, from these results it can be inferred that the PSC can be further evaluated as a potential gene carrier for the kidney-targeted delivery of therapeutic genes for treating diseases.

      • IR 780-loaded hyaluronic acid micelles for enhanced tumor-targeted photothermal therapy

        Uthaman, Saji,Mathew, Ansuja Pulickal,Park, Hyeong Ju,Lee, Byeong-Il,Kim, Hyung-Seok,Huh, Kang Moo,Park, In-Kyu Elsevier 2018 Carbohydrate polymers Vol.181 No.-

        <P><B>Abstract</B></P> <P>In this study, we propose using IR 780-loaded, CD44-targeted hyaluronic acid-based micelles (HA-IR 780) for enhanced photothermal therapy (PTT) effects in tumors. Two kinds of HA-C18 micelles were synthesized from different C18 feed ratios with degree of substitution of 3% and 13% respectively. Three different IR 780 weight percentages were used for micelle formation with loading content of 4.6%, 7.9%, and 10.3% respectively. The IC<SUB>50</SUB> value of HA-IR 780 in TC1 cells was 21.89μgmL<SUP>−1</SUP> (32.81μM). Upon irradiation of the tumor site with an 808-nm laser (2Wcm<SUP>−2</SUP>) for 2min, the temperature in the tumor in the HA-IR 780-treated groups reached 49.9°C which exceeds the temperature threshold to induce irreversible tissue damage. Toxicity studies showed that HA-IR 780 does not cause any adverse effects in organs, including heart, liver, lungs, kidney and spleen, although it selectively caused cell damage in the tumor region upon laser irradiation. Therefore, the present study suggests that HA-IR 780 can cause selective cell death in tumor regions due to its enhanced tumor-targeting and photothermal capabilities.</P> <P><B>Highlights</B></P> <P> <UL> <LI> IR 780-loaded hyaluronic acid-based micelles (HA-IR 780) for photothermal therapy. </LI> <LI> Intravenously administered HA-IR 780 selectively accumulated in tumors by 24h. </LI> <LI> HA-IR 780 exhibited CD44- and EPR-based tumor accumulation. </LI> <LI> Upon irradiation HA-IR 780 causes photothermic ablation in tumor region. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

      • SCIESCOPUSKCI등재
      • KCI등재

        Role of Immunosuppressive Microenvironment in Acquiring Immunotolerance Post-Photothermal Therapy

        Kondareddy Cherukula,박명숙,Adonijah Graham Sontyana,Ansuja Pulickal Mathew,Veena Vijayan,배우균,박인규 대한의학회 2019 Journal of Korean medical science Vol.34 No.44

        Background: Nanoparticle-mediated photothermal therapy (PTT) has been well studied as a treatment for cancer. However, the therapeutic outcome of PTT is often hindered by the penetration depth of laser light. In the tumor margin beyond the laser penetration limit, tumor recurrence often occurs, bypassing the immune response of the host. Accumulating evidence suggests the prominent role of tumor microenvironment (TME) and its interactions with the immune components contribute to an immunosuppressive milieu during the post- therapy period. Here, we explored the immunosuppressive cascade generated after PTT, which is responsible for tumor recurrence, and identified the potential targets to achieve an effective PTT period. Methods: Here, we investigated the immunosuppressive cascade generated after PTT in a CT26 tumor bearing mouse. The liposomal system loaded with the indocyanine green (ICG) was utilized for the generation of PTT with high efficiency. Immunological factors such as cytokines and protein expressions post-therapy were investigated through enzyme-linked immunosorbent assay, flow cytometry and western blot analysis. Results: Our results suggested that PTT with ICG-loaded liposomes (Lipo-ICG) was effective for the first 5 days after treatment, resulting in tumor suppression. However, an immunosuppressive and pro-inflammatory environment developed thereafter, causing the recruitment and upregulation of the immune evasion factors of heat shock protein 70, programmed death ligand 1, indoleamine-dioxygenase, interleukin-6, transforming growth factor-β, regulatory T-cells, and myeloid-derived suppressor cells, to develop immunotolerance. Conclusion: Collectively, these findings have determined potential therapeutic targets to modulate the TME during PTT and achieve tumor ablation without remission.

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