Polymeric micelles containing cationic gemini quaternary ammonium (GQA) groups have shown enhanced cellular uptake and efficient drug delivery, while the incorporation of poly(ethylene glycol) (PEG) corona can potentially reduce the absorption of cationic carriers by opsonic proteins and subsequent uptake by mononuclear phagocytic system (MPS). To understand the interactions of GQA and PEG groups and their effects on the biophysicochemical characteristics of nanocarriers, a series of polyurethane micelles containing GQA and different molecular weights of PEG were prepared and carefully characterized. It was found that the GQA and PEG groups are unevenly distributed on the micellar surface to form two kinds of hydrophilic domains. As a result, the particle surface with some defects cannot be completely shielded by the PEG corona. Despite this, the longer PEG chains with a brush conformation provide superior stabilization and steric repulsion against the absorption of proteins and, thus, can reduce the cytotoxicity, protein absorption, and MPS uptake of micelles to some extent. This study provides a new understanding on the interactions between PEG chains and cationic groups and a guideline for the design and fabrication of safe and effective drug delivery systems.
Cationic gemini quaternary ammonium (GQA) has been used as a cell internalization promoter to improve the permeability of the cell membrane and enhance the cellular uptake. However, the effect of the alkyl chain length on the cellular properties of nanocarriers has not been elucidated yet. In this study, we developed a series of polyurethane micelles containing GQAs with various alkyl chain lengths. The alteration of the gemini alkyl chain length was found to change the distribution of GQA surfactants in the micellar structure and affect the surface charge exposure, stability, and the protein absorption properties of nanocarriers. Moreover, we also clarified the role of the alkyl chain length in tumor cell internalization and macrophage uptake of polyurethane micelles. This work provides a new understanding on the effect of the GQA alkyl chain length on the physicochemical and biological properties of nanomedicines, and offers guidance on the rational design of effective drug delivery systems where the issue of functional group exposure at the micellar surface should be considered.
Cationic
nanocarriers have emerged as promising nanoparticle systems for the
effective delivery of nucleic acid and anticancer drugs to cancer
cells. A positive charge is desirable for promoting cell internalization,
whereas it also causes some adverse effects, such as toxicity and
rapid clearance by mononuclear phagocytic systems. Herein, a new strategy
of modifying cationic polymer micelles with albumin forming a protein
corona to improve the surface physiochemical properties is reported.
The corona with a monolayer or a multilayer was constructed depending
on the albumin concentration, and the proteins would denature in different
degrees due to the interaction with the surface of cationic micelles.
It is demonstrated that multilayer albumin corona is beneficial to
prevent macrophage uptake, increase accumulation in tumor tissues,
and reduce toxic side effects to normal tissues. Our work provides
a promising method to modify the cationic nanoplatform by optimizing
the biosecurity and bioavailability for potential application in drug
delivery.
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