Octreotide-conjugated PAMAM for targeted delivery to somatostatin receptors over-expressed tumor cells.
OBJECTIVE
An octreotide-conjugated polyamidoamine (PAMAM) dendrimer was synthesized and employed as nanocarriers of methotrexate (MTX), for targeting to the somatostatin receptors over-expressed tumor cells.


METHODS
PAMAM-PEG-octreotide (PPO) and PAMAM-PEG (PPG) were synthesized and characterized. The cellular uptake of fluorescein isothiocyanate (FITC)-labeled PPO (PPO-FITC) and PPG (PPG-FITC) were investigated. The cytotoxicity of MTX and MTX nanoparticles were conducted in the MCF-7 cells. Besides, the pharmacokinetics studies on MTX nanoparticles were carried out in rats.


RESULTS
The structure of PPO was verified by NMR detection and the diameter was 11.05 ± 1.80 nm, with the amount of MTX encapsulated by PPO was 30 (molecule/molecule). MTX nanoparticles possessed significantly higher cytotoxicity against MCF-7 cells compared with free MTX, especially the PPO/MTX nanoparticles. Correspondingly, the PPO-FITC carrier had higher cellular uptake efficiency compared to PPG-FITC. In addition, pharmacokinetics studies showed that PPO/MTX nanoparticles increased mean residence time and bioavailability of MTX distinctly.


CONCLUSIONS
With further cellular uptake test of FITC-labeled carriers, the enhanced cytotoxicity of PPO/MTX nanoparticles was reasonable to ascribe to the specific receptor-mediated endocytosis induced by octreotide. The present study suggests that this PAMAM-PEG-octreotide nanocarrier opens a new path for treating cancer with higher efficacy.
Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University , Nanjing, Jiangsu , PR China .
Jianqing
J
Peng
Xiaole
X
Qi
Yi
Y
Chen
Ning
N
Ma
Ziwei
Z
Zhang
Jiaxu
J
Xing
Xuehua
X
Zhu
Zhengrong
Z
Li
Zhenghong
Z
Wu
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000009:adverse effects / Q000737:chemistry*; D004337:Drug Carriers / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry*; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D015282:Octreotide / Q000009:adverse effects / Q000737:chemistry*; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000096:biosynthesis*; D013499:Surface Properties
D000964:Antimetabolites, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D017481:Receptors, Somatostatin; D015282:Octreotide; D008727:Methotrexate
Methotrexate; octreotide; polyamidoamine; receptor-mediated endocytosis; tumor targeting