Hyaluronic acid-capped compact silica-supported mesoporous titania nanoparticles for ligand-directed delivery of doxorubicin

Gupta, Biki,Poudel, Bijay Kumar,Ruttala, Hima Bindu,Regmi, Shobha,Pathak, Shiva,Gautam, Milan,Jin, Sung Giu,Jeong, Jee-Heon,Choi, Han-Gon,Ku, Sae Kwang,Yong, Chul Soon,Kim, Jong Oh Elsevier 2018 ACTA BIOMATERIALIA Vol.80 No.-

<P><B>Abstract</B></P> <P>Mesoporous titania nanoparticles (MTN), owing to their high surface area to volume ratio and tunable pore sizes, appear capable of delivering sizable amounts of drug payloads, and hence, show considerable promise as drug delivery candidates in cancer therapy. We designed silica-supported MTN (MTNst) coated with hyaluronic acid (HA) to effectively deliver doxorubicin (DOX) for breast cancer therapy. The HA coating served a dual purpose of stabilizing the payload in the carriers as well as actively targeting the nanodevices to CD44 receptors. The so-formed HA-coated MTNst carrying DOX (HA/DOX-MTNst) had spheroid particles with a considerable drug-loading capacity and showed significantly superior in vitro cytotoxicity against MDA-MB-231 cells as compared to free DOX. HA/DOX-MTNst markedly improved the cellular uptake of DOX in an apparently CD44 receptor-dependent manner, and increased the number of apoptotic cells as compared to free DOX. These nanoplatforms accumulated in large quantities in the tumors of MDA-MB-231 xenograft tumor-bearing mice, where they significantly enhanced the inhibition of tumor growth compared to that observed with free DOX with no signs of acute toxicity. Based on these excellent results, we deduced that HA/DOX-MTNst could be successfully used for targeted breast cancer therapy.</P> <P><B>Statement of Significance</B></P> <P>This is the first study to use silica-supported mesoporous titania nanoparticles (MTNst) for doxorubicin (DOX) delivery to treat breast cancer, which exhibited effective and enhanced in vitro and in vivo apoptosis and tumor growth inhibition. Solid silica was used to support the mesoporous TiO<SUB>2</SUB> resulting in MTNst, which efficiently incorporated a high DOX payload. The hyaluronic acid (HA) coating over the MTNst surface served a dual purpose of first, stabilizing DOX inside the MTNst (capping agent), and second, directing the nanoplatform device to CD44 receptors that are highly expressed in MDA-MB-231 cells (targeting ligand). The NPs exhibited highly efficacious in vitro tumor-cell killing and excellent in vivo tumor regression, highlighting the enormous promise of this system for breast cancer therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Recent progress in cancer immunotherapy approaches based on nanoparticle delivery devices

Gupta Biki,김종오 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.4

Background Immunotherapy is a rapidly emerging approach to cancer therapy that focuses on empowering the immune system by countering the mechanisms whereby cancer cells frequently evade immunosurveillance and negate anticancer immune responses. However, there are major challenges to successful implementation of immunotherapy approaches in cancer treatment, mainly due to a lack of targetability and inefficient delivery of immunotherapeutics at the target site. Area covered The current review focuses on various anticancer immunotherapy approaches that have recently been investigated and employed, as well as on nanoparticle-based delivery techniques for immunotherapeutics that are being implemented as strategic approaches to overcome the limitations of cancer immunotherapy. Expert opinion Nanoparticle-based delivery techniques for immunotherapeutics have shown immense potential in effective targeting and efficient delivery of these agents at target sites, resulting in effective repression of the immune-evasive mechanisms employed by cancer cells, thereby significantly inducing immune-mediated cancer cell killing and inhibition of tumor proliferation and metastasis. Further understanding of cancer immunology and investigations into enhancing the specificity and targetability of nanoparticle delivery devices can lead to clinical success of nanoparticle-based immunotherapy approaches in cancer treatment.

Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers.

Gupta, Biki,Poudel, Bijay Kumar,Tran, Tuan Hiep,Pradhan, Roshan,Cho, Hyuk-Jun,Jeong, Jee-Heon,Shin, Beom Soo,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Kluwer Academic/Plenum Publishers 2015 Pharmaceutical research Vol.32 No.9

<P>To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics.</P>

Efffects of Formulation Variables on the Pariticle Size and Drug Encapsulation of Imatinib-Loaded Solid Lipid Nanoparticles

( Biki Gupta ),( Bijay Kumar Poudel ),( Shiva Pathak ),( Jin Wook Tak ),( Hee Hyun Lee ),( Jee Heon Jeong ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-Ioaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experi-mental design. IMT-SLN was optimized by use of a "combo" approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (OIL), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S,), drug loading (DL), and encapsulation efficiency (EE) of 1M`` I`` SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A=O.04, D/L=O.03, and Tw20=2.50%wlv. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0±0.9 nm, ζ-potential of -24.2±1.2 mV, and DL and EE of 2.9±0.1 and 97.6±0.1%w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.

Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors

Gupta, Biki,Ramasamy, Thiruganesh,Poudel, Bijay Kumar,Pathak, Shiva,Regmi, Shobha,Choi, Ju Yeon,Son, Youlim,Thapa, Raj Kumar,Jeong, Jee-Heon,Kim, Jae Ryong,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh American Chemical Society 2017 ACS APPLIED MATERIALS & INTERFACES Vol.9 No.11

<P>Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.</P>

Medicinal Chemistry : RESEARCH PAPER ; Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers

( Biki Gupta ),( Bijay Kumar Poudel ),( Tuan Hiep Tran ),( Roshan Pradhan ),( Hyuk Jun Cho ),( Jee Heon Jeong ),( Beom Soo Shin ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

Purpose To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics. Methods IMT-NLC was prepared by hot homogenization method, and optimized by an approach involving Plackett-Burman design (PBD) and central composite design (CCD). An in vivo pharmacokinetic study was conducted in rats after both oral and intravenous administration. The in vitro cytotoxicity was evaluated by MTTassay on NCI-H727 cell-lines. Results PBD screening, followed by optimization by CCD and desirability function, yielded an optimized condition of 0.054, 6% w/w, 2.5%w/w and 1.25%w/v for organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), amount of lecithin (Lec) and amount of Tween® 20 (Tw20) respectively. The optimized IMT-NLC exhibited a particle size (Sz) of 148.80±1.37 nm, polydispersity index (PDI) 0.191±0.017 of and ζ-potential of .23.0 ±1.5 mV, with a drug loading (DL) of 5.48±0.01% and encapsulation efficiency (EE) of 97.93±0.03%. IMT-NLC displayed sustained IMTrelease in vitro, significantly enhanced in vivo bioavailability of IMTafter intravenous and oral administration, and greater in vitro cytotoxicity on NCI-H727 cells, compared with free IMT. Conclusion A combined DoE approach enabled accurate optimization and successful preparation of IMT-NLC with enhanced in vivo pharmacokinetic and in vitro cytotoxicity characteristics.

Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy

Gupta, Biki,Ruttala, Hima Bindu,Poudel, Bijay Kumar,Pathak, Shiva,Regmi, Shobha,Gautam, Milan,Poudel, Kishwor,Sung, Min Hyun,Ou, Wenquan,Jin, Sung Giu,Jeong, Jee-Heon,Ku, Sae Kwang,Choi, Han-Gon,Yong, American Chemical Society 2018 ACS APPLIED MATERIALS & INTERFACES Vol.10 No.29

<P>Cellular Fas-associated protein with death domain-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.</P> [FIG OMISSION]</BR>

Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin

Gupta, Biki,Pathak, Shiva,Poudel, Bijay Kumar,Regmi, Shobha,Ruttala, Hima Bindu,Gautam, Milan,Lee, Jong Seong,Jeong, Jee-Heon,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier 2017 Colloids and surfaces Biointerfaces Vol.155 No.-

<P><B>Abstract</B></P> <P>When exposed to cancer cells, cytotoxic drugs such as doxorubicin (DOX) can lead to the induction of heat shock protein 90 (Hsp90), a molecular chaperone associated with a number of cancer-related client proteins, and result in cell survival. Co-administration of DOX with tanespimycin (TNP), an Hsp90 inhibitor, can sensitize the cancer cells to the cytotoxic effects of DOX. The effect of such a combination has been found to depend on the schedule of administration. Sequential administration of DOX and TNP has been linked to highly synergistic combination effects. Therefore, we aimed to develop folate-receptor targeted hybrid lipid-core nanocapsules comprising a hybrid lipid core lodging TNP and a polymeric corona lodging DOX (F-DTN). These nanocarriers were capable of delivering DOX and TNP sequentially, which was well demonstrated by an <I>in vitro</I> release study. The <I>in vitro</I> release profiles displayed pH-dependent and sustained release features. F-DTN exhibited excellent morphological characteristics with highly monodispersed particles. <I>In vitro</I> tests with F-DTN in MCF-7 cell line demonstrated exceptional cytotoxicity, with high cellular uptake and apoptosis. These findings were appreciably more assertive than tests with free individual drugs (DOX, TNP), free drug combination (DOX/TNP), or non-folate receptor-targeted hybrid lipid-core nanocapsules (DTN). <I>In vivo</I> pharmacokinetic study revealed noticeable enhancement of bioavailability and plasma circulation time of the drugs when encapsulated in the carrier system. Therefore, hybrid lipid-core nanocapsules have the potential to be utilized for application in folate receptor-targeted combination chemotherapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Hybrid lipid-core nanocapsules for doxorubicin and tanespimycin sequential delivery. </LI> <LI> Sequential, pH-dependent, and sustained release characteristics. </LI> <LI> Highly monodispersed spherical nanoparticles with excellent morphology. </LI> <LI> Exceptional cytotoxicity with high cellular uptake and apoptosis in MCF-7 cells. </LI> <LI> Increased bioavailability and plasma circulation in Sprague-Dawley rats. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Employing an optimized spray-drying process to produce ezetimibe tablets with an improved dissolution profile

김성엽,김종오,Biki Gupta,문철,오의철,정지헌,용철순 한국약제학회 2016 Journal of Pharmaceutical Investigation Vol.46 No.6

Ezetimibe is a low-density lipoprotein cholesterol- lowering agent with poor aqueous solubility. There is therefore a need to increase the aqueous solubility of ezetimibe in order to improve its dissolution profile, and thereby, enhance its bioavailability. The purpose of this study was to produce a solid dispersion of ezetimibe with improved physicochemical characteristics, which could be then be used to prepare ezetimibe tablets with improved dissolution characteristics. The ezetimibe solid dispersion was prepared by an optimized spray-drying process. Product characteristics, namely, yield, moisture content, solubility, and Hausner ratio, were optimized by controlling process parameters, namely, inlet temperature, pump feed rate, and solid contents, by applying the Box-Behnken design and the desirability functions approach. The physicochemical characteristics of the optimized solid dispersion were in close agreement with the predicted characteristics. The tablets formulated using the optimized solid dispersion exhibited an excellent dissolution profile, which was remarkably better than that of tablets formulated from free ezetimibe or a physical mixture of the drug and the excipients. Therefore, ezetimibe tablets with improved solubility and dissolution characteristics were produced using an optimized spray-drying technique.

Preparation of High-Payload, Prolonged-Release Biodegradable Poly(lactic-co-goycolic acid)-Based Tacrolimus Microspheres Using the Singel-Jet Electrospray Method

( Shiva Pathak ),( Biki Gupta ),( Bijay Kumar Poudel ),( Tuan Hiep Tran ),( Shibha Regmi ),( Tung Thanh Pham ),( Raj Kumar Thapa ),( Min Soo Kim ),( Chul Soon Yong ),( Jong Oh Kim ),( Jee Heon Jeong ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-

Tacrolimus-loaded poly(lactic-co-glycolic acid) micro spheres (TAC-PLGA-M) can be administered for the long-term survival of transplanted organs due to their immunosuppressive activity. The purpose of our study was to optimize the parameters of the clcctrospray method, and to prepare T AC-PLGA-M with a high payload and desirable release properties. TAC-PLGA-M were prepared using the electrospray method. III vitro characterization and evaluation were performed using scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Drug-loading efficiency was greater than 80% in all formulations with a maximum loading capacity of 16.81±0.37%. XRD and DSC studies suggested that the drug was incorporated in an amorphous state or was molecularly dispersed in the microspheres. The ill vitro release study showed prolonged release patterns. TAC-PLGA-M with enhanced drug loading and prolonged-release patterns were successfully prepared using the electro-spray method.