Dexamethasone Phosphate-Loaded Folate-Conjugated Polymeric Nanoparticles for Selective Delivery to Activated Macrophages and Suppression of Inflammatory Responses

Jiafu Cao,유진욱,Muhammad Naeem,노진기,이은희 한국고분자학회 2015 Macromolecular Research Vol.23 No.5

Activated macrophages play a central role in the pathology of inflammatory diseases by secreting proinflammatory cytokines. In this study, we have developed folate-conjugated dexamethasone phosphate (DP)-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) that can selectively target to activated macrophages for alleviation of inflammatory responses. DP was loaded into PLGA nanoparticles in an amorphous form using an ionic interaction between DP, zinc, and PLGA. Folic acid (FA) was used as a targeting ligand for activated macrophages and conjugated onto DPNPs (FA-DPNPs). The mean particle size of DPNPs and FA-DPNPs was 126±36 and 133±28 nm, respectively. The zeta potential of DPNPs and FA-DPNPs were -13.5±0.4 mV and -14.9±0.9 mV, respectively. Sustained and controlled DP release over 48 hours from DPNPs and FA-DPNPs was observed. The low cellular uptake of both DPNPs and FA-DPNPs was observed in normal RAW264.7 macrophages, whereas significantly higher cellular uptake of FA-DPNPs was observed as compared to DPNPs in activated RAW264.7 macrophages. The production of pro-inflammatory cytokines (IL-6 and TNF-α) and nitric oxide (NO) from activated macrophages was inhibited more significantly by FA-DPNPs than by free DP and DPNPs. Taken together, DP-loaded nanoparticles, especially when conjugated with FA, were selectively internalized by activated macrophages and effectively suppressed inflammatory responses. DP loaded folate-conjugated PLGA nanoparticles presented in this study may offer a promising approach of targeted delivery to activated macrophages for the treatment of inflammatory diseases.

Enhanced therapeutic efficacy of budesonide in experimental colitis with enzyme/pH dual-sensitive polymeric nanoparticles

Naeem, Muhammad,Cao, Jiafu,Choi, Moonjeong,Kim, Woo Seong,Moon, Hyung Ryong,Lee, Bok Luel,Kim, Min-Soo,Jung, Yunjin,Yoo, Jin-Wook Dove Medical Press 2015 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.10 No.-

<P>Current colon-targeted drug-delivery approaches for colitis therapy often utilize single pH-triggered systems, which are less reliable due to the variation of gut pH in individuals and in disease conditions. Herein, we prepared budesonide-loaded dual-sensitive nanoparticles using enzyme-sensitive azo-polyurethane and pH-sensitive methacrylate copolymer for the treatment of colitis. The therapeutic potential of the enzyme/pH dual-sensitive nanoparticles was evaluated using a rat colitis model and compared to single pH-triggered nanoparticles. Clinical activity scores, colon/body weight ratios, myeloperoxidase activity, and proinflammatory cytokine levels were markedly decreased by dual-sensitive nanoparticles compared to single pH-triggered nanoparticles and budesonide solution. Moreover, dual-sensitive nanoparticles accumulated selectively in inflamed segments of the colon. In addition, dual-sensitive nanoparticle plasma concentrations were lower than single pH-triggered nanoparticles, and no noticeable in vitro or in vivo toxicity was observed. Our results demonstrate that enzyme/pH dual-sensitive nanoparticles are an effective and safe colon-targeted delivery system for colitis therapy.</P>

Development of clindamycin-loaded alginate/pectin/hyaluronic acid composite hydrogel film for the treatment of MRSA-infected wounds

핫산 눌하스니,Cao Jiafu,이주호,김현우,유진욱 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.5

Purpose Methicillin-resistant Staphylococcus aureus (MRSA) infection on wounds possesses a high risk in increased cases of morbidity and mortality worldwide. Antibiotic-loaded composite biopolymer film wound dressings are one approach to cover the chronic wound area, promote the healing process, and create suitable healing environments. In this study, we developed clindamycin (Cly)-loaded composite biopolymer films using hydrogel-forming biopolymers, such as sodium alginate (SA), pectin (P), and hyaluronic acid (HA) for the treatment of MRSA-infected wounds. Methods Composite films were prepared using a solvent casting method. Cly-loaded composites hydrogel films were evaluated for their physical properties (e.g., film thickness, surface morphology, pH, water vapor transmission, expansion profile, and fluid uptake), in vitro drug release, in vitro bactericidal effects, and in vivo wound healing activity in an ICR mouse model of MRSA-infected wounds. Results Thin, transparent, and highly absorbent Cly-loaded SA-P (Cly/SA-P) and Cly-loaded SA-P-HA (Cly/SA-P-HA) film dressings were successfully prepared with good physical properties. The Cly/SA-P and Cly/SA-P-HA films exhibited drug release over 12 h under immersed conditions and potent antibacterial activity against MRSA (> 5 log reduction in bacterial viability). Furthermore, compared with the other groups, the Cly/SA-P-HA-treated group significantly accelerated the healing and re-epithelialization of wounds in a mouse model of MRSA-infected wounds. All prepared film dressings were not toxic to healthy fibroblast cells. Conclusion Thus, the Cly-loaded composite hydrogel film prepared in this study could be a promising wound dressing for the treatment of infected cutaneous wounds.

Recent advancements of nitric oxide-releasing hydrogels for wound dressing applications

Hasan Nurhasni,Jiafu Cao,Mustopa Apon Zaenal,Himawan Achmad,Umami Rifqiyah Nur,Ullah Muneeb,Wathoni Nasrul,유진욱 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.6

Background Hydrogels are three-dimensional (3D) polymer networks that can absorb significant volumes of water inside their interstices and continue connecting these interstices while maintaining an inflated network structure; this capability is due to their unusual 3D crosslinked polymer meshwork structure. Hydrogels are promising wound dressings, particularly for chronic wounds, owing to their wound-healing properties, such as flexibility, adhesion, moisture control, biocompatibility, and biodegradability. Nitric oxide (NO) is a small molecule that has been thoroughly investigated for its wound-healing activity. The diverse roles of NO in wound healing require its stable delivery to the wound site. Thus, hydrogels have been evaluated as promising scaffolds for storing and releasing NO in a controlled manner to promote and accelerate wound healing. Area covered This review sought to introduce the types of polymers used to prepare hydrogel-based wound dressings and the types of NO donors used as wound healing promoters. The preparation method of the hydrogels and their physical and chemical properties were presented herein, and recent studies on NO-releasing hydrogels for wound therapy were summarized and discussed. Selected hydrogels with unique characteristics and significant findings for wound healing were also emphasized. Expert opinion Owing to the importance of chronic wounds in healthcare, the development of functional materials that support proper and rapid wound healing is required. NO-releasing hydrogels can be employed for wound dressing applications owing to their controlled NO releasability and antibacterial and wound healing activities.

A three-dimensional assemblage of gingiva-derived mesenchymal stem cells and NO-releasing microspheres for improved differentiation

Regmi, Shobha,Cao, Jiafu,Pathak, Shiva,Gupta, Biki,Kumar Poudel, Bijay,Tung, Pham Thanh,Yook, Simmyung,Park, Jun-Beom,Yong, Chul Soon,Kim, Jong Oh,Yoo, Jin-Wook,Jeong, Jee-Heon Elsevier 2017 International journal of pharmaceutics Vol.520 No.1

<P><B>Abstract</B></P> <P>Stem cell therapy is an attractive approach to bone tissue regeneration. Nitric oxide (NO) has been reported to facilitate osteogenic differentiation of stem cells. To enhance osteogenic differentiation of gingiva-derived mesenchymal stem cells (GMSCs), we designed a method for <I>in situ</I> delivery of exogenous NO to these cells. A NO donor, polyethylenimine/NONOate, was incorporated into poly(lactic-co-glycolic acid) microspheres to deliver NO to the cells for an extended period of time under <I>in vitro</I> culture conditions. A hybrid aggregate of GMSCs and NO-releasing microspheres was prepared by the hanging drop technique. Confocal microscopy revealed homogeneous arrangement of the stem cells and microspheres in heterospheroids. Western blot analysis and live–dead imaging showed no significant change in cell viability. Importantly, the <I>in situ</I> delivery of NO within the heterospheroids enhanced osteogenic differentiation indicated by a 1.2-fold increase in alkaline phosphatase activity and an approximately 10% increase in alizarin red staining. In addition, a low dose of NO promoted proliferation of the GMSCs in this 3D system. Thus, delivery of the NO-releasing microsphers to induce differentiation of stem cells within this three dimensional system may be one of possible strategies to direct differentiation of a stem cell-based therapeutic agent toward a specific lineage.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Nitric oxide-releasing poly(lactic- <i>co</i> -glycolic acid)-polyethylenimine nanoparticles for prolonged nitric oxide release, antibacterial efficacy, and in vivo wound healing activity

Nurhasni, Hasan,Cao, Jiafu,Choi, Moonjeong,Kim, Il,Lee, Bok Luel,Jung, Yunjin,Yoo, Jin-Wook Dove Medical Press 2015 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.10 No.-

<P>Nitric oxide (NO)-releasing nanoparticles (NPs) have emerged as a wound healing enhancer and a novel antibacterial agent that can circumvent antibiotic resistance. However, the NO release from NPs over extended periods of time is still inadequate for clinical application. In this study, we developed NO-releasing poly(lactic-<I>co</I>-glycolic acid)-polyethylenimine (PEI) NPs (NO/PPNPs) composed of poly(lactic-<I>co</I>-glycolic acid) and PEI/diazeniumdiolate (PEI/NONOate) for prolonged NO release, antibacterial efficacy, and wound healing activity. Successful preparation of PEI/NONOate was confirmed by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, and ultraviolet/visible spectrophotometry. NO/PPNPs were characterized by particle size, surface charge, and NO loading. The NO/PPNPs showed a prolonged NO release profile over 6 days without any burst release. The NO/PPNPs exhibited potent bactericidal efficacy against methicillin-resistant <I>Staphylococcus aureus</I> (MRSA) and <I>Pseudomonas aeruginosa</I> concentration-dependently and showed the ability to bind on the surface of the bacteria. We also found that the NO released from the NO/PPNPs mediates bactericidal efficacy and is not toxic to healthy fibroblast cells. Furthermore, NO/PPNPs accelerated wound healing and epithelialization in a mouse model of a MRSA-infected wound. Therefore, our results suggest that the NO/PPNPs presented in this study could be a suitable approach for treating wounds and various skin infections.</P>

Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy

Naeem, Muhammad,Choi, Moonjeong,Cao, Jiafu,Lee, Yujeong,Ikram, Muhammad,Yoon, Sik,Lee, Jaewon,Moon, Hyung Ryong,Kim, Min-Soo,Jung, Yunjin,Yoo, Jin-Wook Dove Medical Press 2015 Drug design, development and therapy Vol.9 No.-

<P>Single pH-dependent drug delivery systems have been widely used for colon-targeted delivery, but their efficiency is often hampered by the variation in gut pH. To overcome the limitation of single pH-dependent delivery systems, in this study, we developed and evaluated the therapeutic potential of budesonide-loaded dual pH/time-dependent nanoparticles (NPs) for the treatment of colitis. Eudragit FS30D was used as a pH-dependent polymer, and Eudragit RS100 as a time-dependent controlled release polymer. Single pH-dependent NPs (pH_NPs), single time-dependent NPs (Time_NPs), and dual pH/time-dependent NPs (pH/Time_NPs) were prepared using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these NPs in gastrointestinal (GI) tract conditions were investigated. The therapeutic potential and in vivo distribution of the NPs were evaluated in a dextran sulfate sodium (DSS)-induced colitis mice model. The pH/Time_NPs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the mice GI tract demonstrated that pH/Time_NPs were more efficiently delivered to the inflamed colon than pH_NPs were. Compared to the single pH_NPs-treated group, the pH/Time_NPs-treated group showed increased body weight and colon length and markedly decreased disease activity index, colon weight/length ratios, histological damage, and inflammatory cell infiltration in colon tissue. Our results demonstrate that the dual pH/time-dependent NPs are an effective oral colon-targeted delivery system for colitis therapy.</P>

Increased therapeutic efficacy of a newly synthesized tyrosinase inhibitor by solid lipid nanoparticles in the topical treatment of hyperpigmentation

Al-Amin, Md,Cao, Jiafu,Naeem, Muhammad,Banna, Hasanul,Kim, Min-Soo,Jung, Yunjin,Chung, Hae Young,Moon, Hyung Ryong,Yoo, Jin-Wook Dove Medical Press 2016 Drug design, development and therapy Vol.10 No.-

<P>Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana–Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation.</P>

Advances in colon-targeted nano-drug delivery systems: challenges and solutions

Muhammad Naeem,Uzma Azeem Awan,Fazli Subhan,Jiafu Cao,Shwe Phyu Hlaing,이주호,임은옥,YunJinJung,유진욱 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.1

Nano-drug delivery systems (NDDS) for colontargeteddrug delivery are an active area of research onlocal diseases aff ecting the colon, such as ulcerative colitis,Crohn’s disease, colon cancer, and for the delivery of peptideor protein drugs and vaccinations. In particular, targetednano-drug delivery to the colon is advantageous for colonspecific diseases because nanoparticles can accumulate indiseased parts, improve the effi cacies of therapeutics, andenable localized treatments, which reduces systemic toxicity. However, there are many hurdles, such as burst drug release,enzyme and acidic degradation of drug and carrier in thestomach, pH variations, mucus entrapment, and systemicuptake in the upper small intestine, which could challengeand compromise the successful delivery of NDDS to thecolon. With advancements in NDDS, it may be possible toovercome these challenges leading to effi cient drug deliveryfor colon-specifi c disorders. This review describes a fewof the potential colon-specifi c drug delivery areas and thechallenges faced by colon-targeted orally administered deliverysystems, and provides an updated summary of recentadvances in the development of orally administered NDDSfor colon targeting, and the future advances in this research.

Phospho sulfonic acid: an efficient and recyclable solid acid catalyst for the solvent-free synthesis of α-hydroxyphosphonates and their anticancer properties

Kalla, Reddi Mohan Naidu,Lee, Hye Ri,Cao, Jiafu,Yoo, Jin-Wook,Kim, Il The Royal Society of Chemistry 2015 New journal of chemistry Vol.39 No.5

<P>As a means of developing biologically active compounds, a series of alpha-hydroxyphosphonates, ArC(OH) PO(OR)(2) (Ar = 5-G-2-OHPh; R = Me, Et, iPr, Bu; G = H, Br, Cl, NO2), have been synthesized by reacting diversely substituted salicylaldehydes with dialkyl phosphites by employing the Pudovik reaction in the presence of phospho sulfonic acid under neat conditions. The cytotoxicity of the compounds was tested in two human cancer cell lines by using MTT assay. Compounds bearing R = Et; G = Cl, R = Bu; G = Cl, and R = Et; G = NO2 showed good anticancer activity.</P>