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Ramasamy, Thiruganesh,Ruttala, Hima Bindu,Chitrapriya, Nataraj,Poudal, Bijay Kumar,Choi, Ju Yeon,Kim, Ssang Tae,Youn, Yu Seok,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier 2017 ACTA BIOMATERIALIA Vol.48 No.-
<P><B>Abstract</B></P> <P>In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-<I>b</I>-poly(<SMALL>L</SMALL>-histidine)-<I>b</I>-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.</P> <P><B>Statement of Significance</B></P> <P>In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehicles as an advanced platform technology for application in cancer therapy. We designed a robust (poly(phenylalanine)-<I>b</I>-poly(<SMALL>L</SMALL>-histidine)-<I>b</I>-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts<I>.</I> In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Ramasamy, Thiruganesh,Sundaramoorthy, Pasupathi,Ruttala, Hima Bindu,Choi, Yongjoo,Shin, Woo Hyun,Jeong, Jee-Heon,Ku, Sae Kwang,Choi, Han-Gon,Kim, Hwan Mook,Yong, Chul Soon,Kim, Jong Oh Informa Healthcare 2017 DRUG DELIVERY Vol.24 No.1
( Thiruganesh Ramasamy ),( Ju Yeon Choi ),( Hyuk Jun Cho ),( Subbaih Kandasamy Umadevi ),( Beom Soo Shin ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Purpose Irinotecan (IRI) is a broad spectrum chemotherapeutic agent used individually or in combination to treat multiple malignancies. Present study aimed at developing polypeptide-based block ionomer complex (BIC) micelles to improve the pharmacokinetic and antitumor response of IRI. Methods Irinotecan-loaded BIC micelles (IRI-BIC) was prepared and evaluated in terms of various physicochemical and biological parameters including size, shape, release, cytotoxicity, and pharmacokinetic analysis. In vivo antitumor efficacy was investigated in SCC-7 bearing xenograft tumor model. Results IRI was successfully incorporated into the ionic cores of poly(ethylene glycol)-b-poly(aspartic acid) (PEG-b-PAA) with a high drug loading capacity (~80%). The electrostatically assembled BIC micelles were nanosized (~50 nm) with uniform size distribution pattern (PDI~0.1). The BIC micelles exhibited pHsensitiveness with limited release of IRI at physiological conditions and significantly enhanced the release rate at acidic conditions, making it an ideal delivery system for tumor targeting. The IRI-BIC showed a dose-dependent cytotoxicity in SCC-7 and A-549 cancer cell lines. Pharmacokinetic studies clearly showed that BIC micelles improved the IRI blood circulation time and decreased its elimination rate constant, while that of free IRI, rapidly eliminated from the central compartment. Moreover, IRI-BIC showed superior therapeutic performance with no toxicity in BALB/c nude xenograft mice. The micelle treated group showed an inhibition rate of ~66% compared to free IRI treated group. Conclusions Taken together, BIC micelles could be a potentially useful nanovehicle with promising applicability in systemic tumor treatment.
Ramasamy, Thiruganesh,Ruttala, Hima Bindu,Sundaramoorthy, Pasupathi,Poudel, Bijay Kumar,Youn, Yu Seok,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Springer Science and Business Media LLC 2018 NPG Asia Materials Vol.10 No.-
( Thiruganesh Ramasamy ),( Tuan Hiep Tran ),( Hyuk Jun Cho ),( Jeong Hwan Kim ),( Yong Ll Kim ),( Jae Yoon Jeon ),( Han Gon Choi ),( Chul Soon Yong ),( Jong Oh Kim ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Purpose: To investigate the effect of polyelectrolytes on the formation and physicochemical properties of chitosan nanoparticles (CS-NPs) used for the delivery of an anticancer drug, doxorubicin (DOX). Method: Three DOX-loaded CS-NPs were formulated with tripolyphosphate (CS-TP/DOX NPs), dextran sulfate (CS-DS/DOX NPs), and hyaluronic acid (CS-HA/DOX NPs) by using ionotropic gelation or complex coacervation. Results: CS-TP/DOX NPs were the smallest, with an average size of ~100 nm and a narrow size distribution, while CS-DS/DOX and CS-HA/DOX NPs were ~200 nm in size. Transmission electron microscopy clearly showed a spherical shape for all the NPs. The strong binding affinity of DOX for the multiple sulfate groups in DS resulted in a sustained release profile from CS-DS/DOX NPs at pH 7.4, while CS-HA/DOX NPs exhibited faster DOX release. This trend was also present under acidic conditions, where release of DOX was significantly augmented because of polymer protonation. Compared to CS-TP/DOX or CS-DS/DOX NPs, CS-HA/DOX NPs showed superior cellular uptake and cytotoxicity in MCF-7 and A-549 cells, because of their ability to undergo CD44-mediated endocytosis. Pharmacokinetic studies clearly showed that all CS-NPs tested significantly improved DOX plasma circulation time and decreased its elimination rate constant. Consistent with the in vitro release data, CS-DS/DOX NPs exhibited a relatively better DOX plasma profile and enhanced blood circulation, compared to CS-HA/DOX or CS-TP/DOX NPs. Overall, these results demonstrated how NP design can influence their function. Conclusions: Taken together, CS-based polyelectrolyte complexes could provide a versatile delivery system with enormous potential in the pharmaceutical and biomedical sectors.
Combination of two or more drugs has emerged as a promising strategy to elicit synergistic therapeutic responses that can overcome multidrug resistance of cancer cells at various stages of the growth cycle. In the current study, we investigated the efficacy of two drugs, mitoxantrone (MTX) and doxorubicin (DOX), co-encapsulated in a polyethylene oxide-b-polyacrylic acid polymer. The resulting block ionomer complex (BIC)-based combination chemotherapy provides a novel method for enhancing the therapeutic efficacy of chemotherapies. The BIC micelles were very stable at physiological pH, and showed a temporally sequenced release profile for the co-encapsulated drugs at tumor pH. This suggests that the micelles can deliver chemotherapeutic agents at the appropriate cellular stage. At a predetermined and carefully controlled ratio (MTX:DOX = 2:1), the two drugs worked synergistically within A549 small lung cancer cells. Taken together, these findings suggest that the synergistic activity of ratiometrically controlled drug combinations can enhance their chemotherapeutic action and overall therapeutic index.
The aim of this study was to formulate and evaluate Ketoconazole-loaded solid lipid nanoparticles (KSLN) for topical application. The purpose of this study was to improve the therapeutic activity of Ketoconazole. KSLN was prepared by a hot homogenization method and characterized for shape, surface morphology, particle size,drug entrapment, cytotoxicity, and rheological analysis. The optimized formulation of solid lipid nanoparticles (SLN) was spherical in shape with a smooth surface and possessed an average size of 172.2±0.75 nm with zeta potential of -44.12±0.76 mV. To guarantee the stability of the desired SLN, they were lyophilized using cryo-protectants. The particle size of the SLN significantly enlarged for formulations which were lyophilized without the cryo-protectants. Cell viability assay performed on National Institute of Health-3-day transfer, inoculum 3×105 cells (NIH-3T3) fibroblast cells showed that properties of the SLN remain unchanged during the process of freeze-drying and were not cytotoxic. An in vitro drug release study showed that KSLN-incorporated hydrogel exhibited a sustained drug release comparing to KSLN dispersion and Ketoconazole loaded hydrogel over a 24 h period. The in vivo studies suggested that the KSLN-incorporated hydrogel was more efficient in the treatment of candidiasis. It may therefore be interpreted that the KSLN-incorporated hydrogel provides a sustained release of Ketoconazole for topical fungal infections and might be a promising delivery system to enhance the therapeutic activity of Ketoconazole.