Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation

Ruttala, Hima Bindu,Ramasamy, Thiruganesh,Poudel, Bijay Kumar,Ruttala, Raghu Ram Teja,Jin, Sung Giu,Choi, Han-Gon,Ku, Sae-Kwang,Yong, Chul Soon,Kim, Jong Oh Elsevier Science B.V. Amsterdam 2020 ACTA BIOMATERIALIA Vol. No.

<P><B>Abstract</B></P> <P>Herein, we developed a multifunctional nanoplatform based on the nanoassembly of gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective cancer treatment. Conjugating AS1411 aptamer on the surface of the nanoparticle significantly improved particle accumulation in cancer cells via specific affinity toward the nucleolin receptors. In vitro study clearly revealed that laser irradiation-based hyperthermia effect enhanced the chemotherapeutic effects of LND. Combinational treatment modalities revealed significant apoptosis with higher cell killing effect due to increased ROS production and inhibition of cell migration. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Moreover, immunohistochemistry staining assays confirmed the ability of AS-LAGN to induce cellular apoptosis/necrosis and ablation in tumor tissues, without causing evident damages to the surrounding healthy tissues. Altogether, this AS-LAGN nanoplatform could be a promising strategy for mitochondria-based cancer treatment.</P> <P><B>Statement of significance</B></P> <P>We have designed a facile biodegradable multifunctional nanocarrier system to target the mitochondria, the major “power house” of the cancer cells. We have constructed a multifunctional nanoassembly of protein coronated gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective combination of phototherapy with chemotherapy for cancer treatment. The LND was conjugated with albumin which was in turn conjugated to GNP via redox-liable disulfide linkage to generate oxidative stress and ROS to kill cancer cells. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Consistently, AS-LAGN showed enhanced antitumor efficacy in xenograft tumor model with remarkable tumor regression property.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy

Ruttala, Hima Bindu,Ko, Young Tag Elsevier 2015 Colloids and surfaces Biointerfaces Vol.128 No.-

<P><B>Abstract</B></P> <P>Paclitaxel (PTX) and curcumin (CUR) are potent chemotherapeutic agents used in the treatment of cancer. In the present study, hybrid polymer–lipid nanoparticles co-loaded with PTX and CUR were developed to investigate the therapeutic potential of a combination drug regimen. For this purpose, PTX-loaded albumin nanoparticles (APN) were prepared and encapsulated in PEGylated hybrid liposomes containing CUR (CL-APN) <I>via</I> a thin-film hydration technique. CL-APN was nanosized with a uniform spherical morphology. PTX and CUR release was sustained and occurred in a sequential manner, wherein CUR was expected to downregulate the nuclear factor NF-κB and Akt pathways and increase the therapeutic efficacy of PTX. The ratiometric combination of PTX and CUR was significantly more cytotoxic than the individual drugs. Importantly, dual-drug-loaded nanocarriers exhibited a superior cytotoxic effect than a cocktail combination at a lower dose. CL-APN induced significantly higher early and late apoptosis, induced a stronger G<SUB>2</SUB>/M arrest, and significantly increased the subG<SUB>1</SUB> cell population. By combining CUR, an effective NF-κB inhibitor, with PTX, a powerful anticancer drug, in a polymer–lipid hybrid nanoparticle system, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Hybrid nanoparticles co-loaded with PTX and CUR enhanced the chemotherapeutic efficiency. </LI> <LI> The ratiometric combination of PTX and CUR induced a stronger G<SUB>2</SUB>/M arrest. </LI> <LI> Co-loaded delivery systems could improve clinical outcomes against various malignancies. </LI> </UL> </P>

Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy

Ruttala, Hima Bindu,Chitrapriya, Natarajan,Kaliraj, Kaliappan,Ramasamy, Thiruganesh,Shin, Woo Hyun,Jeong, Jee-Heon,Kim, Jae Ryong,Ku, Sae Kwang,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier Science B.V. Amsterdam 2017 ACTA BIOMATERIALIA Vol. No.

<P><B>Abstract</B></P> <P>In this study, we developed pH and redox-responsive crosslinked polypeptide-based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-<I>b</I>-poly(aspartic acid)-<I>b</I>-poly(tyrosine) (PEG-<I>b</I>-pAsp-<I>b</I>-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy.</P> <P><B>Statement of Significance</B></P> <P>We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-<I>b</I>-poly(aspartic acid)-<I>b</I>-poly(tyrosine) (PEG-<I>b</I>-pAsp-<I>b</I>-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem for the effective synergistic delivery of DTX/LND in tumor tissues towards cancer treatment.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Liposome Encapsulated Albumin-Paclitaxel Nanoparticle for Enhanced Antitumor Efficacy

Ruttala, H. B.,Ko, Y. T. Springer Science + Business Media 2015 Pharmaceutical research Vol.32 No.3

Layer-by-layer assembly of hierarchical nanoarchitectures to enhance the systemic performance of nanoparticle albumin-bound paclitaxel

Ruttala, Hima Bindu,Ramasamy, Thiruganesh,Shin, Beom Soo,Choi, Han-Gon,Yong, Chul Soon,Kim, Jong Oh Elsevier 2017 International journal of pharmaceutics Vol.519 No.1

<P><B>Abstract</B></P> <P>Although protein-bound paclitaxel (PTX, Abraxane<SUP>®</SUP>) has been established as a standard PTX-based therapy against multiple cancers, its clinical success is limited by unfavorable pharmacokinetics, suboptimal biodistribution, and acute toxicities. In the present study, we aimed to apply the principles of a layer-by-layer (LbL) technique to improve the poor colloidal stability and pharmacokinetic pattern of nanoparticle albumin-bound paclitaxel (<I>nab</I>-PTX). LbL-based <I>nab</I>-PTX was successfully fabricated by the alternate deposition of polyarginine (pARG) and poly(ethylene glycol)-block-poly (L-aspartic acid) (PEG-<I>b</I>-PLD) onto an albumin conjugate. The presence of protective entanglement by polyamino acids prevented the dissociation of <I>nab</I>-PTX and improved its colloidal stability even at a 100-fold dilution. The combined effect of high nanoparticle internalization and controlled release of PTX from LbL-<I>nab</I>-PTX increased its cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cells. LbL-<I>nab</I>-PTX consistently induced apoptosis in approximately 52% and 22% of MCF-7 and MDA-MB-231 cancer cells, respectively. LbL assembly of polypeptides effectively prevented exposure of PTX to the systemic environment and thereby inhibited drug-induced hemolysis. Most importantly, LbL assembly of polypeptides to nab-PTX effectively increased the blood circulation potential of PTX and improved therapeutic efficacy via a significantly higher area under the curve (AUC)<SUB>0–∞</SUB>. We report for the first time the application of LbL functional architectures for improving the systemic performance of <I>nab</I>-PTX with a view toward its clinical translation for cancer therapy.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting

Ruttala, H.B.,Ramasamy, T.,Gupta, B.,Choi, H.G.,Yong, C.S.,Kim, J.O. Applied Science Publishers ; Elsevier Science Ltd 2017 Carbohydrate Polymers Vol.173 No.-

In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy.

Emerging potential of stimulus-responsive nanosized anticancer drug delivery systems for systemic applications

Hima Bindu Ruttala,Thiruganesh Ramasamy,Thiagarajan Madeshwaran,Tran Tuan Hiep,Umadevi Kandasamy,오경택,최한곤,용철순,김종오 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.2

The development of novel drug delivery systemsbased on well-defined polymer therapeutics has led tosignificant improvements in the treatment of multiple disorders. Advances in material chemistry, nanotechnology,and nanomedicine have revolutionized the practices ofdrug delivery. Stimulus-responsive material-based nanosizeddrug delivery systems have remarkable propertiesthat allow them to circumvent biological barriers andachieve targeted intracellular drug delivery. Specifically,the development of novel nanocarrier-based therapeutics isthe need of the hour in managing complex diseases. In thisreview, we have briefly described the fundamentals of drugtargeting to diseased tissues, physiological barriers in thehuman body, and the mechanisms/modes of drug-loadedcarrier systems. To that end, this review serves as acomprehensive overview of the recent developments instimulus-responsive drug delivery systems, with focus ontheir potential applications and impact on the future of drugdelivery.

Evaluation of antimicrobial effect of DA-5502 in gingivitis and periodontal diseases

Hima Bindu Ruttala,강민경,박형근,용철순,전준호,김종오 한국약제학회 2018 Journal of Pharmaceutical Investigation Vol.48 No.4

The aim of present study was to examine the bactericidal and antimicrobial activity of novel DA-5502 in gingivitis and periodontal diseases. The in vitro antimicrobial activity of DA-5502 was investigated against two strains Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans by biofilm and planktonic method. DA-5502 effectively inhibited both the biofilm formation and oral bacteria in planktonic state for both P. gingivalis and A. actinomycetemcomitans strains, which results in reduction of plaque and gum inflammation. The in vitro results provide scientific evidence that our novel DA-5502 liquid dentifrice formulation composed of cetylpyridinium chloride, dipotassium glycyrrhizinate, and panthenol as main active pharmaceutical ingredients, has effective adsorption capacity with excellent antimicrobial, antigingivitis, and antiplaque activity to treat periodontal diseases.

Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

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>

Engineering of a lipid-polymer nanoarchitectural platform for highly effective combination therapy of doxorubicin and irinotecan

Ramasamy, T.,Ruttala, H. B.,Choi, J. Y.,Tran, T. H.,Kim, J. H.,Ku, S. K.,Choi, H. G.,Yong, C. S.,Kim, J. O. The Royal Society of Chemistry 2015 Chemical communications Vol.51 No.26

<P>We developed a highly stable lipid-polymer nanoarchitectural platform for effective combination therapy of doxorubicin and irinotecan in the polyelectrolyte complex nanoparticle core, followed by incorporation of the whole assembly into a lecithin bilayer. It shows great potential for the treatment of a broad range of cancers.</P> <P>Graphic Abstract</P><P>We developed a highly stable lipid-polymer nanoarchitectural platform for effective combination therapy of doxorubicin and irinotecan in the polyelectrolyte complex nanoparticle core, followed by incorporation of the whole assembly into a lecithin bilayer. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c5cc00482a'> </P>