Journal
MOLECULAR PHARMACEUTICS
Volume 10, Issue 5, Pages 1695-1704Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp300522p
Keywords
polyamidoamine dendrimer; nanoparticulate drug carrier; pH-sensitive; surface protection; zwitterionic chitosan
Funding
- NSF [DMR-1056997]
- NIH [R21 CA135130]
- Lilly Endowment, Inc.
- NIH/NCRR-Indiana Clinical and Translational Sciences Institute Predoctoral Fellowship [TL1 RR025759]
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Polyamidoamine (PAMAM) dendrimers have been widely explored as carriers of therapeutics and imaging agents. However, amine-terminated PAMAM dendrimers are rarely utilized in systemic applications due to their cytotoxicity and risk of opsonization, caused by their cationic charges. Such undesirable effects may be mitigated by shielding the PAMAM dendrimer surface with polymers that reduce the charges. However, this shielding may also interfere with the PAMAM dendrimers' ability to interact with target cells, thus reducing the cellular uptake and overall efficacy of the delivery system. Therefore, we propose to use zwitterionic chitosan (ZWC), a new chitosan derivative, which has a unique pH-sensitive charge profile, as an alternative biomaterial to modify the cationic surface of PAMAM dendrimers. A stable electrostatic complex of ZWC and PAMAM dendrimers was formed at pH 7.4, where the PAMAM dendrimer surface was covered with ZWC, as demonstrated by fluorescence spectroscopy and transmission electron microscopy. The presence of ZWC coating protected red blood cells and fibroblast cells from hemolytic and cytotoxic activities of PAMAM dendrimers, respectively. Confocal microscopy showed that the protective effect of ZWC disappeared at low pH as the complex dissociated due to the charge conversion of ZWC, allowing PAMAM dendrimers to enter cells. These results demonstrate that ZWC is able to provide a surface coverage of PAMAM dendrimers in a pH-dependent manner and, thus, enhance the utility of PAMAM dendrimers as a drug carrier to solid tumors with acidifying microenvironments.
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