The effect of size and polymer architecture of doxorubicin-poly(ethylene) glycol conjugate nanocarriers on breast duct retention, potency and toxicity.
Eur J Pharm Sci
; 121: 118-125, 2018 08 30.
Article
in En
| MEDLINE
| ID: mdl-29698706
ABSTRACT
Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol-doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40â¯kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half-lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40â¯kDa PEG-(DOX)4 (1.23⯵M)â¯<â¯5â¯kDa PEG-DOX (1.76⯵M)â¯<â¯40â¯kDa PEG-(DOX)8 (3.49⯵M)â¯<â¯10â¯kDa PEG-DOX (3.86⯵M)â¯<â¯20â¯kDa PEG-DOX (8.96⯵M)â¯<â¯40â¯kDa PEG-DOX (18.11⯵M), whereas the IC50 of free DOX was only 0.14⯵M. The t1/2 of linear 5, 20, and 40â¯kDa nanocarriers were 2.2⯱â¯0.3, 3.6⯱â¯0.6, and 13.1⯱â¯3.4â¯h, whereas the retention t1/2 of 4- and 8-arm 40â¯kDa nanocarriers were 14.9⯱â¯5.6â¯h and 11.9⯱â¯2.9â¯h, respectively. The retention t1/2 of free doxorubicin was 2.0⯱â¯0.4â¯h, which was significantly shorter than that of the linear and branched 40â¯kDa PEG-DOX nanocarriers. Increased molecular weight and decreased branching both demonstrated a strong correlation to enhanced mammary gland retention. Intraductally administered free doxorubicin resulted in ductal damage, severe inflammation and generation of atypical cell neoplasms, whereas PEG-DOX nanocarriers induced only minor and transient inflammation (i.e., damaged epithelial cells and detached cellular debris). The 40â¯kDa 4-arm PEG-DOX nanocarrier demonstrated the longest ductal retention half-life, the lowest IC50 (i.e., most potent), and minimal ductal damage and inflammation. The current results suggest that PEG-DOX nanocarriers with prolonged ductal retention may present the best option for intraductal treatment of DCIS, due to their low local toxicity and potential for sustained therapeutic effect.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polyethylene Glycols
/
Drug Carriers
/
Doxorubicin
/
Nanostructures
/
Mammary Glands, Animal
/
Antineoplastic Agents
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Eur J Pharm Sci
Journal subject:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Year:
2018
Type:
Article