Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles.
OBJECTIVE
The matrix metalloproteinase (MMP) 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs) ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL) by inserting a gelatinase cleavable peptide (PVGLIG) between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery.


METHODS
mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs) prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted.


RESULTS
The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel) as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs.


CONCLUSIONS
The results in this study preliminarily demonstrated the effectiveness of gelatinase-responsive targeting strategy and the prospect of this intelligent nano-drug delivery system though further studies are needed.
The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, PR China.
Rutian
R
Li
Wei
W
Wu
Qin
Q
Liu
Puyuan
P
Wu
Li
L
Xie
Zhenshu
Z
Zhu
Mi
M
Yang
Xiaoping
X
Qian
Yin
Y
Ding
Lixia
L
Yu
Xiqun
X
Jiang
Wenxian
W
Guan
Baorui
B
Liu
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D018093:Gelatinases / Q000737:chemistry; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D010455:Peptides; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; D018093:Gelatinases