Effect of the Structure of Therapeutic Adenosine Analogues on Stability and Surface Electrostatic Potential of their Complexes with Poly(propyleneimine) Dendrimers

Abstract

Poly(propyleneimine) glycodendrimers are proposed as nanocarriers for triphosphate forms of anticancer adenosine analogues to improve the efficiency of chemotherapy and to overcome drug resistance mechanisms. This approach has proven successful for fludarabine administration—an autonomous way of cellular entry of a nucleotide–dendrimer noncovalent complex enables an increase in the intracellular accumulation and cytotoxic activity of the active metabolite of the drug. However, the attempt to apply an analogous strategy for clofarabine results in the inhibition of drug activity. To better understand this phenomenon, characterization and comparison of drug‐dendrimer complexes were needed to indicate the differences in their surface properties and the strengths of fludarabine‐dendrimer and clofarabine‐dendrimer interactions. Here, zeta potential measurements, ultrafiltration, and asymmetric flow field‐flow fractionation are applied to determine the surface electrostatic potential and stability of nucleotide–dendrimer formulations. This approach significantly extends the authors’ research on the complexation potential of perfectly branched macromolecules, ultimately explaining previously observed differences and their consequences.

Asymmetric flow field-flow fractionation as a multifunctional technique for the characterization of polymeric nanocarriers

“…Conversely, drug transfer could be physically possible during the focusing step, where donors and acceptors are pressed on each other by the cross-flow; this is compensated by the fact that the timescale of the focusing is much shorter (4–10 min) [ 129 ]. Especially in cases when drug release is medium-sensitive, the composition of the eluent should match the release medium, to prevent undesired drug release or reassociation [ 173 ].…”

Recent advances in development of dendritic polymer‐based nanomedicines for cancer diagnosis

“…Their degree of branching is determined by NMR spectra and tandem mass spectrometry (Maniego et al, 2019; Mao et al, 2019). Fourier transform infrared and titrimetry have been used to characterize their surface chemistry (Gorzkiewicz et al, 2019; Nguyen et al, 2019). Basic properties and structures of dendritic polymers, such as multiple functional groups, excellent water‐solubility, low viscosity, biocompatibility, biodegradability, and stimuli‐responsiveness, endow them with great potential in various applications in the bio‐related field, including but not limited to drug/gene delivery, cancer diagnosis, tissue regeneration, and theranostics (K. Chen, Liao, Guo, Zhang, et al, 2018; Dai et al, 2018; L. Li, Wang, C., Huang, et al, 2018; Pan, Guo, Luo, Yi, & Gu, 2014).…”

Noncovalent Interactions with PAMAM and PPI Dendrimers Promote the Cellular Uptake and Photodynamic Activity of Rose Bengal: The Role of the Dendrimer Structure

“… 16 − 18 Because complex formation is usually based on ionic interactions, the process itself, as well as the physicochemical and biological properties of dendrimer/drug complexes, is greatly influenced by pH; ionic strength; buffer composition; and, most importantly, the structure of the dendritic carriers. 19 , 20 …”

“…However, although dendrimer/drug conjugates are generally more stable in solutions and in vivo , the use of covalent linkers can drastically alter the photosensitive properties of PS, thus decreasing its phototoxicity . Therefore, numerous studies on the use of nanoparticles, including dendrimers, as RB carriers have focused on noncovalent interactions, demonstrating the efficient intracellular uptake and superior photodynamic properties of such formulations. − Because complex formation is usually based on ionic interactions, the process itself, as well as the physicochemical and biological properties of dendrimer/drug complexes, is greatly influenced by pH; ionic strength; buffer composition; and, most importantly, the structure of the dendritic carriers. , …”