A pH-sensitive hyaluronic acid prodrug modified with lactoferrin for glioma dual-targeted treatment.
Gliomas are the most common and lethal type of primary malignant brain tumor. But the existence of blood brain barrier (BBB) and blood-tumor barrier (BTB) hinder drug from reaching the tumor site. To address this problem, we developed a novel prodrug (Lf-HA-DOX) by conjugating hyaluronic acid with doxorubicin (HA-DOX) by an acid-labile hydrazone linkage, which is released in an acidic environment and accumulates in tumor tissues. Lactoferrin (Lf) was coupled for transporting across the BBB. In vitro, the release of DOX from Lf-HA-DOX was pH-dependent. At lower pH (5.0 and 6.0), the release of DOX was much quicker than that at pH7.4. In the cellular uptake studies, flow cytometry analyses and confocal laser scanning microscopy results showed significantly enhanced cellular uptake of Lf-HA-DOX and HA-DOX in C6 cells compared to DOX. In BALB/C mice bearing C6 glioma, enhanced accumulation of Lf-HA-DOX in the glioma was observed by real time fluorescence image. Correspondingly, glioma-bearing mice treated with Lf-HA-DOX displayed the longest median survival time, which was 2-fold longer than that of saline group. In conclusion, Lf-HA-DOX was able to significantly increase drug delivery to the glioma, which might provide a promising strategy for antiglioma therapy.
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Yatao
Y
Yin
PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Chaoping
C
Fu
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Mei
M
Li
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Xiangpen
X
Li
PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Mengying
M
Wang
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Lei
L
He
PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China; School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China. Electronic address: ceszhlm@mail.sysu.edu.cn.
Li-Ming
LM
Zhang
Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: docpengy123@163.com.
Ying
Y
Peng
D000818:Animals; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007781:Lactoferrin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D023041:Xenograft Model Antitumor Assays
D003692:Delayed-Action Preparations; D011355:Prodrugs; D004317:Doxorubicin; D006820:Hyaluronic Acid; D007781:Lactoferrin
Doxorubicin; Glioma; Hyaluronic acid; Lactoferrin; Prodrug; Targeted treatment