Influence of dendrimer surface charge on the bioactivity of 2-methoxyestradiol complexed with dendrimers

Abstract

We report the complexation of a potential anticancer agent 2-methoxyestradiol (2-ME) with generation 5 (G5) poly(amidoamine) dendrimers having different surface functional groups for therapeutic applications. The complexation experiment shows that approximately 6–8 drug molecules can be complexed with one dendrimer molecule regardless the type of the dendrimer terminal groups. The bioactivity of 2-ME complexed with dendrimers was found to be significantly dependent on the surface charge of G5 dendrimers. In vitro cell biological assays show that amine, hydroxyl, and acetamide-terminated G5 dendrimers with positive, slightly positive, and close to neutral surface charges, respectively are able to deliver 2-ME to inhibit cancer cell growth. In contrast, 2-ME complexed with carboxyl-terminated G5 dendrimers with negative surface charges does not show its inherent bioactivity. Further molecular dynamics simulation studies show that the compact structure of carboxylated G5 dendrimers complexed with 2-ME does not allow the release of the drug molecules even at a pH of 5.0, which is the typical pH value in lysosome. Our findings indicate that the surface modification of dendrimers with different charges is crucial for the development of formulations of various anticancer drugs for therapeutic applications.

Multiscale Modeling for Host-Guest Chemistry of Dendrimers in Solution

“…The types of guest molecules considered in this review will include low molecular weight organic molecules [24,29,50,51], and nucleic acids [38,[69][70][71][72][73]. The review of interactions of dendrimers with lipid membrane has been clearly explained in Reference [37].…”

“…Shi and coworkers studied 2-methoxyestradiol (2-ME), a potential anticancer agent, with modified PAMAM dendrimers at pH 5. The terminal group chemistries that were considered included amine, acetyl, hydroxyl, and carboxyl groups [51]. All-atom molecular dynamics using the CVFF force field for PAMAM and 2-ME and an implicit model for water were used to model the binding positions of 2-ME molecules in the dendrimer.…”

“…For this reason, the FMO approach is most effective when it is coupled with methods such as docking or classical molecular dynamics to model the interaction of dendrimers with guest molecules. At the next higher scales of calculation, all-atom and mesoscale simulations have been widely applied to study the binding mechanism of dendrimers with guest molecules [24,38,39,[48][49][50][51]. There are two main approaches for mesoscale simulations: coarse-grained "particle-based" simulations and statistical field theories.…”

Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy

“…43 The change in surface potential of both the dendrimers and complexes with pH followed the same trend as that of the G5.NHAc dendrimers described in our previous work. 25 In addition, the G5.NHAc-FI-FA/ CA4 complexes in aqueous solution (eg, water, phosphatebuffered saline buffer with a pH value of 7.4, and cell culture medium) stored at 4°C were stable for at least 12 months ( Figure S2), which is again essential for their further biological applications. conditions, three kinds of phosphate buffer (20 mM) with different pHs (pH 7.4, pH 6.8, and pH 6.0) were selected as release media.…”

“…23,24 The internal hydrophobic cavities of dendrimers are able to encapsulate hydrophobic anticancer drugs, such as doxorubicin and 2-methoxyestradiol, and release the drug in a sustained manner. [25][26][27][28][29] In the meantime, the abundant functional groups on the dendrimer surface can covalently link with imaging agents, targeting ligands, and therapeutic drugs for simultaneous imaging, targeting, and treatment of cancer cells. [30][31][32][33][34][35] Therefore, for drug delivery applications, PAMAM dendrimers can be used either to encapsulate hydrophobic drugs physically within the dendrimer interior or as a platform to link drug molecules covalently on their surface.…”