PMID- 31305836
OWN - NLM
STAT- MEDLINE
DCOM- 20191226
LR  - 20231111
IS  - 2040-3372 (Electronic)
IS  - 2040-3364 (Print)
IS  - 2040-3364 (Linking)
VI  - 11
IP  - 29
DP  - 2019 Aug 7
TI  - Enhancing chemoradiation of colorectal cancer through targeted delivery of 
      raltitrexed by hyaluronic acid coated nanoparticles.
PG  - 13947-13960
LID - 10.1039/c9nr04320a [doi]
AB  - Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase 
      inhibitor, and radiation can lead to improved outcome for rectal cancer patients. 
      To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) 
      coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. 
      These particles were determined to have a diameter of  approximately 115 nm, with a 
      polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 
      cells determined through flow cytometry showed a  approximately 5-fold increase between 
      untargeted and HA-coated particles. Through viability and DNA damage assays, we 
      assessed the potency of the free RTX and HARPs, and found increased DNA damage in 
      cells treated with the RTX-loaded nanoparticles administered concurrently with 
      radiation. In vivo efficacy through tumor growth inhibition was investigated in a 
      syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute 
      toxicity in vivo, and all treatments showed survival benefits for their 
      respective groups compared to controls. HARPs alone slowed tumor growth, although 
      not significantly. Radiation alone and in combination with the HARPs showed 
      significant growth delay. Notably, the combination treatment significantly 
      hindered tumor progression relative to the HARPs highlighting the benefit of this 
      multipronged treatment. These results provide a foundation for loading RTX in a 
      nanoparticle formulation, and establish a combined radiation and drug dosing 
      schedule to determine optimal tumor growth delay and subsequent treatment 
      efficacy.
FAU - Rosch, Justin G
AU  - Rosch JG
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State 
      University, Portland, OR 97201, USA.
FAU - Landry, Madeleine R
AU  - Landry MR
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State 
      University, Portland, OR 97201, USA.
FAU - Thomas, Charles R Jr
AU  - Thomas CR Jr
AD  - Department of Radiation Medicine, School of Medicine, Oregon Health & Science 
      University, Portland, OR 97239, USA. sunc@ohsu.edu.
FAU - Sun, Conroy
AU  - Sun C
AUID- ORCID: 0000-0001-5193-6907
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State 
      University, Portland, OR 97201, USA and Department of Radiation Medicine, School 
      of Medicine, Oregon Health & Science University, Portland, OR 97239, USA. 
      sunc@ohsu.edu.
LA  - eng
GR  - R35 GM119839/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20190715
PL  - England
TA  - Nanoscale
JT  - Nanoscale
JID - 101525249
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Drug Carriers)
RN  - 0 (Histones)
RN  - 0 (Quinazolines)
RN  - 0 (Thiophenes)
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - FCB9EGG971 (raltitrexed)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/*chemistry/pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Colorectal Neoplasms/drug therapy/mortality/pathology/radiotherapy
MH  - DNA Damage/drug effects
MH  - Drug Carriers/*chemistry/metabolism
MH  - Histones/metabolism
MH  - Humans
MH  - Hyaluronic Acid/*chemistry
MH  - Kaplan-Meier Estimate
MH  - Liver/drug effects/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Nanoparticles/*chemistry/metabolism
MH  - Quinazolines/*chemistry/pharmacology/therapeutic use
MH  - Radiation, Ionizing
MH  - Thiophenes/*chemistry/pharmacology/therapeutic use
MH  - Transplantation, Heterologous
PMC - PMC7213297
MID - NIHMS1584161
COIS- Competing Interests The authors declare that they have no competing interests.
EDAT- 2019/07/16 06:00
MHDA- 2019/12/27 06:00
PMCR- 2020/08/07
CRDT- 2019/07/16 06:00
PHST- 2019/07/16 06:00 [pubmed]
PHST- 2019/12/27 06:00 [medline]
PHST- 2019/07/16 06:00 [entrez]
PHST- 2020/08/07 00:00 [pmc-release]
AID - 10.1039/c9nr04320a [doi]
PST - ppublish
SO  - Nanoscale. 2019 Aug 7;11(29):13947-13960. doi: 10.1039/c9nr04320a. Epub 2019 Jul 
      15.