Treatment of chemotherapy-induced neutropenia in a rat model by using multiple daily doses of oral administration of G-CSF-containing nanoparticles.
Chemotherapy-induced neutropenia often increases the likelihood of life-threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(γ-glutamic acid) conjugated with diethylene triamine pentaacetic acid (γPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of γPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy.
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Fang-Yi
FY
Su
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Er-Yuan
EY
Chuang
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Po-Yen
PY
Lin
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Yi-Chun
YC
Chou
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan, ROC.
Chiung-Tong
CT
Chen
Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Fwu-Long
FL
Mi
Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC.
Shiaw-Pyng
SP
Wey
Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
Tzu-Chen
TC
Yen
Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan, ROC; Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC. Electronic address: lin4857@adm.cgmh.org.tw.
Kun-Ju
KJ
Lin
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address: hwsung@che.nthu.edu.tw.
Hsing-Wen
HW
Sung
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D048271:Chitosan / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005947:Glucose / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009503:Neutropenia / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010316:Particle Size; D004369:Pentetic Acid / Q000737:chemistry; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D049268:Positron-Emission Tomography; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D055672:Static Electricity; D014018:Tissue Distribution / Q000187:drug effects; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D000970:Antineoplastic Agents; C511775:poly(gamma-glutamic acid); D016179:Granulocyte Colony-Stimulating Factor; D011099:Polyglutamic Acid; D004369:Pentetic Acid; D048271:Chitosan; D005947:Glucose
Biodistribution; Chemotherapy-induced neutropenia; Glucose utilization; Oral protein delivery; Translational medicine