PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation.
OBJECTIVE
To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system.


METHODS
Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging.


RESULTS
DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells.


CONCLUSIONS
The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.
Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, Shanghai, 201203, China.
Saijie
S
Zhu
Minghuang
M
Hong
Lihong
L
Zhang
Guotao
G
Tang
Yanyan
Y
Jiang
Yuanying
Y
Pei
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004339:Drug Compounding / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013696:Temperature
D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000255:Adenosine Triphosphate