title: Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors.
abstract: In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(l-histidine)-b-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.
  
  
  
  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)-b-poly(l-histidine)-b-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. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Thiruganesh
authors: T
authors: Ramasamy
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Hima Bindu
authors: HB
authors: Ruttala
authors: Biophysical Chemistry Lab, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Nataraj
authors: N
authors: Chitrapriya
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Bijay Kumar
authors: BK
authors: Poudal
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Ju Yeon
authors: JY
authors: Choi
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea.
authors: Ssang Tae
authors: ST
authors: Kim
authors: School of Pharmacy, SungKyunKwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon, 440-746, Republic of Korea.
authors: Yu Seok
authors: YS
authors: Youn
authors: College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
authors: Sae Kwang
authors: SK
authors: Ku
authors: College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea. Electronic address: hangon@hangon.ac.kr.
authors: Han-Gon
authors: HG
authors: Choi
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea. Electronic address: csyong@ynu.ac.kr.
authors: Chul Soon
authors: CS
authors: Yong
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, Republic of Korea. Electronic address: jongohkim@yu.ac.kr.
authors: Jong Oh
authors: JO
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D057446:Hydrodynamics; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D010455:Peptides; D011794:Quercetin; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D023822:Tissue Engineering / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D054852:Small Molecule Libraries; D004317:Doxorubicin; D011794:Quercetin
keywords: Combination; Doxorubicin; Nanovehicle; Polypeptide; Quercetin