Preparation, Characterization, and Release Study of Tacrolimus-Loaded Liquid Crystalline Nanoparticles

( Raj Kumar Thapa ),( Rengarajan Baskaran ),( Thiagarajan Madheswaran ),( Jong Oh Kim ),( Chul Soon Yong ),( Bong Kyu Yoo ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0

The use of liquid crystalline nanoparticles is a novel approach in the field of controlled drug delivery. Tacrolimus, being a highly lipophilic dug, is easily incorporated in the hydrophobic core of these nanoparticles, which are prepared using monoolein, distilled water, and varying ratios of poloxamer 407. Characterization, including transmission electron microscopy (TEM) images, particle size, and entrapment efficieney analysis suggested the formation of cubosomes with a particke size ranging from 140 to 155 nm and entrapment level of tacrolimus as high as 99% or above. In vitro release studies, revealed a sustained release of tacrolimus for 2 weeks, with a high stability profile of nanoparticles and incorporated drug during the storage period. Therefore, it suggests the possible use of tacrolimus-loaded formulation for intradermal delivery can be useful in the treatment of locally affecting autoimmune skin disease such as psoriasis.

Receptor-targeted, drug-loaded, functionalized graphene oxides for chemotherapy and photothermal therapy

( Raj Kumar Thapa ),( Ju Yeon Choi ),( Bijay Kumar Poudel ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Cancer is one of the leading causes of death worldwide. Although different chemotherapeutic agents have been developed to treat cancers, their use can be limited by low cellular uptake, drug resistance, and side effects. Hence, targeted drug delivery systems are continually being developed in order to improve the efficacy of chemotherapeutic agents. The main aim of this study was to prepare folic acid (F A)-conjugated polyvinyl pyrrolidone-functionalized graphene oxides (GO) (FA-GO) for targeted delivery of sorafenib (SF). GO were prepared using a modified Hummer``s method and subsequently altered to prepare FA-GO and SF-loaded FA-GO (FA-GO/SF). Characterization of GO derivatives was done using ultraviolet/ visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, atomic force microscopy, zeta potential measurements, and determination of in vitro drug release. Hemo-lytic toxicity, in vitro cytotoxicity, cellular uptake, and apoptotic effects of FA-GO/SF were also investigated. The results revealed that GO was successfully synthesized and that further transformation to FA-GO improved the stability and SF drug-loading capacity. In addition, the enhanced SF release under acidic conditions suggested possible benefits for cancer treatment. Conjugation of FA within the FA-GO/SF delivery system enabled targeted delivery of SF to cancer cells expressing high levels of FA receptors, thus increasing the cellular uptake and apoptotic effects of SF. Furthermore, the photothermal effect achieved by exposure of GO to near-infrared irradiation enhanced the anticancer effects ofF A-GO/SF. Taken together, FA-GO/SF is a potential carrier for targeted delivery of chemotherapeutic agents in cancer.

Palladium nanoparticle-decorated 2-D graphene oxide for effective photodynamic and photothermal therapy of prostate solid tumors

Thapa, Raj Kumar,Soe, Zar Chi,Ou, Wenquan,Poudel, Kishwor,Jeong, Jee-Heon,Jin, Sung Giu,Ku, Sae Kwang,Choi, Han-Gon,Lee, You Mie,Yong, Chul Soon,Kim, Jong Oh Elsevier 2018 Colloids and Surfaces B Vol.169 No.-

<P><B>Abstract</B></P> <P>Intratumoral injection of nanoparticles is a viable alternative for treating solid tumors. In this study, we used intratumorally-injected palladium nanoparticle (Pd NP)-decorated graphene oxide (GO) (GO-Pd NPs) for the treatment of solid prostate tumors. GO was synthesized using the modified Hummer’s method and GO-Pd NPs were prepared using the one pot synthesis method. Studies on physicochemical characterization and <I>in vitro/in vivo</I> anticancer properties were performed using GO-Pd NPs. Successful preparation of GO-Pd NPs was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Compared to GO or Pd NPs alone, GO-Pd NPs showed higher cytotoxic effects in prostate cancer 3 (PC3) cells. Irradiation of treated cells with near infrared (NIR) laser considerably enhanced apoptosis induced by synergistic photothermal effect and reactive oxygen species (ROS) generation. Intratumorally-injected GO-Pd NPs showed promising <I>in vivo</I> localized distribution, photothermal ablation, and anti-tumor effects in the PC3 xenograft mouse model. Furthermore, the minimal organ toxicity of GO-Pd NPs was an added advantage. Hence, GO-Pd NPs could be a potential formulation for localized treatment of prostate solid tumors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> GO-Pd NPs were successfully prepared. </LI> <LI> Higher cytotoxic effects were evident in PC3 prostate cancer cells. </LI> <LI> GO-Pd NPs showed the enhanced anti-tumor effects with minimal organ toxicities. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Easy on-demand self-assembly of lateral nanodimensional hybrid graphene oxide flakes for near-infrared-induced chemothermal therapy

Thapa, Raj Kumar,Byeon, Jeong Hoon,Ku, Sae Kwang,Yong, Chul Soon,Kim, Jong Oh Nature Publishing Group 2017 NPG Asia Materials Vol.9 No.8

<P>Near-infrared (NIR)-induced chemothermal doxorubicin (DOX) release for anticancer activity was demonstrated using DOX-incorporated fully lateral nanodimensional graphene oxide (nGO) flakes layered with chitosan-polyethylene glycol (PEG) conjugate (nGO@DOX-cPEG) from a single-pass gas-phase self-assembly. Unlike most previously reported graphene oxide-based drug carriers, the proposed processing method introduced a fully nanoscale (both in lateral dimension and thickness) configuration without multistep wet physicochemical processes that enhance the drug-loading capacity and NIR-induced heat generation resulting from the increased surface area. The accumulation of nGO@DOX-cPEG flakes in prostate cancer cells enhanced apoptotic phenomena via the combined effects of DOX release and heat generation upon NIR irradiation. The combined anticancer effects were verified through in vivo assessment with better safety profiles than free DOX. The proposed strategy warrants continuous assembly of multimodal nanocarriers for the efficient treatment of prostate cancers and may be a promising candidate for advanced drug delivery systems.</P>

Multilayer-Coated Liquid Crystalline Nanoparticles for Effective Sorafenib Delivery to Hepatocellular Carcinoma

( Raj Kumar Thapa ),( Ju Yeon Choi ),( Bijay K Poudel ),( Tran Tuan Hiep ),( Shiva Pathak ),( Biki Gupta ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Hepatocellular carcinoma is one of the most common cancers in adults and develops due to activation of oncogenes and inactivation of tumor suppressor genes. Sorafenib (SF) is a U.S. Food and Drug Administration (FDA) approved drug for the treatment of hepatocellular carcinoma. However, its clinical use is limited by its poor aqueous solubility and undesirable side effects. Monoolein-based liquid crystalline nanoparticles (LCN) are self-assembled structures that have been determined as promising drug-delivery vehicles. Therefore, the main aim of this study was to prepare layer-by-Iayer (LbL) polymer-assembled SF-loaded LCNs (LbL-LCN/SF) for effective delivery of SF to hepatocellular carcinoma. Results revealed that LbL-LCN/SF presented optimum particle size (~165 nm) and polydispersity index (PDl, ~O.l4) with appropriate polymer layer assembly confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Furthermore, LbL-LCN/SF effectively controlled burst release and exhibited pH-sensitive release of SF, thereby increasing drug release in the acidic microenvironment of tumor cells. Compared to free SF and bare LCN, the hemolytic activity of LbL-LCN/SF was significantly reduced (p < om). Interestingly, LbL-LCN/SF was more cytotoxic to HepG2 cells than the free drug was. Additionally, high cellular uptake and greater apoptotic effects of LbL-LCN/SF in HepG2 cells indicates superior antitomor effects. Therefore, LbL-LCN/SF is a potentially effective formulation for hepatocellular carcinoma.

Graphene oxide-wrapped PEGylated liquid crystalline nanoparticles for effective chemo-photothermal therapy of metastatic prostate cancer cells

( Raj Kumar Thapa ),( Yu Seok Youn ),( Jee Heon Jeong ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Here, we report the preparation of PEGylated liquid crystalline nanoparticles (LCN) loaded with docetaxel (DTX) and wrapped with grapheme oxide (GO), called PEG-GO/LCN/DTX, for effective chemo-photothermal therapy of metastatic prostate cancer cells. The prepared formulation exhibited a small particle size(<250 nm), high durg loading capacity(~15%), and efficient near infrared (NIR) light-induced thermal heat. Importantly, PEG-GO/LCN/DTX successfully accumulated in prostate cancer cells and exhib-ited potent apoptotic and actimigration effects, mediated by the combination of the anticancer effects of DTX and the thermal heat induced by exposure of GO to NIR light. Taken together, our findings sup-port that PEG-GO/LCN/DTX may be an effective system for treatment of metastatic prostate cancer. Moreover, the results establish a proof-of-concept for the potential chemo-photothermal functional-ity of PEG-GO/LCN/DTX. This hybrid system of LCN and GO could provide controlled and tatgeted drug delivery with enhanced NIR-induced thermal effects for effective treatment of metastatic cancers.

Hydrophobic binding peptide-conjugated hybrid lipid-mesoporous silica nanoparticles for effective chemo-photothermal therapy of pancreatic cancer

Thapa, Raj Kumar,Nguyen, Hanh Thuy,Gautam, Milan,Shrestha, Aarajana,Lee, Eung Seok,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Informa Healthcare 2017 DRUG DELIVERY Vol. No.

Analysis and optimization of drug solubility to improve pharmacokinetics

Raj Kumar Thapa,최한곤,용철순,김종오 한국약제학회 2017 Journal of Pharmaceutical Investigation Vol.47 No.2

Solubility measurement is one of the key elements that need to be considered in drug discovery and development process. Hence, its appropriate analysis and optimization is necessary to enhance the drug’s pharmacokinetic and therapeutic effects. In this article, different methods used for solubility analysis and optimization such as shake flask, potentiometric, turbidimetric, computational, miniature device and high throughput automated methods have been summarized. Additionally, the effect of solubility optimization methods (physical, chemical and carrier technology modifications) on pharmacokinetic enhancement has also been elucidated. New fast, feasible and automated methods of solubility analysis are necessary for its accurate measurement as well as for minimization of errors posed by traditional methods. Among the physical, chemical and carrier modification methods; higher potential is exhibited by nanoparticulate drug delivery carriers for optimization of drug solubility and enhancement of pharmacokinetics. Based on the drug characteristics and delivery requirement, appropriate method can be chosen for efficient solubility and pharmacokinetics enhancement of lipophilic drugs, especially of BCS class II and class IV.

Nanomedicine-based antimicrobial peptide delivery for bacterial infections: recent advances and future prospects

Thapa Raj Kumar,Diep Dzung B.,Tønnesen Hanne Hjorth 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.4

Background Antimicrobial peptides (AMPs) have gained wide interest as viable alternatives to antibiotics owing to their potent antimicrobial effects and the low propensity of resistance development. However, their physicochemical properties (solubility, charge, hydrophobicity/hydrophilicity), stability issues (proteolytic or enzymatic degradation, aggregation, chemical degradation), and toxicities (interactions with blood components or cellular toxicities) limit their therapeutic applications. Area covered Nanomedicine-based therapeutic delivery is an emerging concept. The AMP loaded nanoparticles have been prepared and investigated for their antimicrobial effects. In this review, we will discuss different nanomedicine-based AMP delivery systems including metallic nanoparticles, lipid nanoparticles, polymeric nanoparticles, and their hybrid systems along with their future prospects for potent antimicrobial efficacy. Expert opinion Nanomedicine-based AMP delivery is a recent approach to the treatment of bacterial infections. The advantageous properties of nanoparticles including the enhancement of AMP stability, controlled release, and targetability make them suitable for the augmentation of AMP activity. Modifications in the nanomedicine-based approach are required to overcome the problems of nanoparticle instability, shorter residence time, and toxicity. Future rigorous studies for both the AMP loaded nanoparticle preparation and characterization, and detailed evaluations of their in vitro and in vivo antimicrobial effects and toxicities, are essential.

Development of ciclopirox nail lacquer with enhanced permeation and retention

Raj Kumar Thapa,최주연,고도경,강민형,한상덕,전준호,손미원,용철순,김종오 대한약학회 2016 Archives of Pharmacal Research Vol.39 No.7

Onychomycosis is a prevailing disease caused by fungal infection of nails that mostly affects athletes and the elderly. Ciclopirox is approved by the US Food and Drug Administration for the topical treatment of onychomycosis. However, the desired penetration of ciclopirox into the nail bed has not been achieved via topical application for efficient treatment. Therefore, the main aim of this study was to enhance ciclopirox permeation and retention in nail by the development of a new nail lacquer formulation. We screened the effects of different solvents, alkalizing agents, and permeation enhancers on the permeation of bovine hooves by ciclopirox and its retention in human nail clippings. The results suggest that isopropyl alcohol, potassium hydroxide, and urea as the solvent, alkalizing agent, and permeation enhancer, respectively, improved the permeation of the ciclopirox nail lacquer formulation the most with high flux rates. Comparison of the final formulation and marketed product revealed enhanced retention of ciclopirox from our developed formulation in human nail clippings. Therefore, our newly developed nail lacquer may be a potentially effective formulation for the treatment of onychomycosis in humans.