Nanoparticles have received enormous attention as a promising tool to enhance target-specific drug delivery and diagnosis. Various in vitro and in vivo techniques are used to characterize a new system and predict its clinical efficacy. These techniques enable efficient comparison across nanoparticles and facilitate a product optimization process. On the other hand, we recognize their limitations as a prediction tool, which owe to inadequate applications and overly simplified test conditions. This article provides a critical review of in vitro and in vivo techniques currently used for evaluation of nanoparticles and introduces emerging techniques and models that may be used complementarily.
Polyamidoamine (PAMAM) dendrimers have been widely explored as carriers of therapeutics and imaging agents. However, amine-terminated PAMAM dendrimers is rarely utilized in systemic applications due to its cytotoxicity and risk of opsonization, caused by its 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 PAMAM dendrimers’ ability to interact with target cells, thus reducing 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. 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 microenvironment.
Nanoparticulate (NP) drug carrier systems are attractive vehicles for selective drug delivery to solid tumors. Ideally, NPs should evade clearance by the reticuloendothelial system while maintaining the ability to interact with tumor cells and facilitate cellular uptake. Great effort has been made to fulfill these design criteria, yielding various types of functionalized NPs. Another important consideration in NP design is the physical and functional stability during circulation, which, if ignored, can significantly undermine the promise of intelligently designed NP drug carriers. This commentary reviews several NP examples with stability issues and their consequences, ending in a discussion of experimental methods for reliable prediction of NP stability.
Nanoscale copolymer membranes that mimic the innate structure and properties of biological lipid membranes possessing hydrophilic and hydrophobic elements to support protein folding were used for a fundamental examination of protein—polymer integration. This study has integrated the neural synaptotagmin II (Syt II) protein, a documented target of the hemagglutinin-33 (Hn-33) protein associated with botulinum neurotoxin type A during the infection process, into polymethyloxazoline—polydimethylsiloxane—polymethyloxazoline nanomembranes. By integrating Syt II into block copolymer membranes, we have developed a neural mimetic membrane toward Hn-33 targeting the applications in nanomaterial-mediated detection. This technology can serve as a robust stand-alone platform for toxin diagnostic studies, or as a coating for integration with micro-/nanofabricated devices and electrodes for protein—protein interaction-based detection. To assess enhanced membrane complexity and toxin specificity, studies assessing the co-insertion of trisialoganglioside-GT1b (GT1b) and Syt II into the nanomembranes were used as a subsequent platform for botulinum neurotoxin type B detection. Protein—membrane integration was confirmed with atomic force microscopy imaging, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Langmuir isotherm analysis.
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