Exploring the trans-membrane dynamic mechanisms of single polyamidoamine nano-drugs via a “force tracing” technique

Abstract

Considerable technological success has been achieved in the drug delivery of nano-drugs for chemotherapy, but the main obstacles in understanding the drug delivery dynamic mechanisms for nano-drug applications stem from technical limitations. In this paper, we explored the trans-membrane dynamic processes of polyamidoamine nano-drugs via a "force tracing" technique.Nanocarriers have been used as intelligent drug delivery systems (DDSs) to signicantly improve the bioavailability of poorly soluble drugs and the efficacy of drugs for clinical treatment.1-6 Among the many nanocarriers, polyamidoamine (PAMAM) dendrimers undoubtedly show a superior performance, attracting researchers' attention, 7 since they have the advantages of non-immunogenicity and a high transport efficiency for carrying bioactive agents.8 In addition, as PAMAM is sensitive to pH, the drug can be released from the interior of the macromolecule via diffusion, so as to achieve a sustained release and enhance the drug efficacy. In contrast to other nanocarriers, PAMAM dendrimers are highly branched synthetic macromolecules obtained via iterative stepwise reaction sequences, 9 and the highly branched structure ensures the facile modication of the dendrimer nanoparticle surface with different therapeutic drugs, diagnostic agents, and targeting ligands.10 The branched structure also makes it easy to conjugate with uorescein isothiocyanate for imaging live cells and tracking the drug carriers.11 The internal molecular cavity of PAMAM provides the ability to physically encase small molecule drugs through electrostatic interactions and/or hydrogen bonding interactions. 12Usually, covalent conjugation and encapsulation are the main methods for loading drugs on PAMAM. E. W. Meijer and coworkers reported that guest molecules were captured within the internal cavities of the dendritic nanoparticles, and that the diffusion of guest molecules out of the carriers into solution was slow because of the close packing of the shell.13 In order to understand the effect of drug loading on the structural properties of the dendrimer, V. Jain et al. used molecular dynamic (MD) simulations to characterize the molecular models of dendrimer-nateglinide encapsulation complexes, and the MD analysis revealed that both the pH value of the solution and the terminal groups of the dendrimer play a part in drug encapsulation efficiency.14 Another effective approach used in drug loading is the covalent conjugation of the drug to the terminal functional groups of the dendrimers.12 Y. Gao et al. successfully conjugated ursolic acid (UA) and folic acid (FA) to PAMAM, and a subsequent cellular uptake study indicated that the presence of FA enhanced the uptake of dendrimeric prodrugs by HeLa cells with over-expressed folate receptors (FRs). This effect could be attributed to FR-mediated endocytosis.15 R. Mohammad et al. developed PAMAM-pullulan conjugates and investigated their targeting activity in delivering genes into liver cells. Furthermore, they assessed the cytotoxicity and tra...

Size‐Independent Transmembrane Transporting of Single Tetrahedral DNA Nanostructures

“…Using the extended worm‐like chain model, the stretched length of the PEG linker could be calculated, which characterizes the force ( F )‐dependent stretching activity by the following equation where k B is the Boltzmann constant, T is the absolute temperature, L p is the persistence length, K 0 is the enthalpic correction, h is the extension of PEG linker, and L 0 is the contour length. Based on the previous literature, the persistence length L p is 3.8 ± 0.02 Å, and the enthalpic correction K 0 is 1561 ± 33 pN. Given that the PEG unit length is 4.2 Å, the estimated contour length L 0 to PEG linker is about 196 Å.…”

“…Herein, the dynamic transmembrane process of TDNs is tracked by force tracing technique based on atomic force microscopy (AFM), the force and duration of the transmembrane transport process of single nanoparticles/molecules could be detected down to pico‐newton and milliseconds, respectively . Combining experiment and simulation, the TDNs size effect on the transmembrane dynamics and protein‐mediated mechanism was explored at single particle level under near physiological condition.…”

Tracking the Single-Carbon-Dot Transmembrane Transport by Force Tracing Based on Atomic Force Microscopy

“…To understand the dynamic transporting process in-depth, another key parameter, the average speed during the process of CDs transmembrane transporting was calculated (displacement divided by duration). Figure displays that the displacement ( D ) of CD transporting includes the bending distance of the AFM tip cantilever ( d ) and the stretching length of the PEG linker ( Q ), as expressed by the following equation. According to the relationship between PEG stretching behavior and the force, the value of Q could be obtained by the extended worm-like chain (WLC) model: Where L p is the persistence length, k B stands for the Boltzmann constant, T refers to the absolute temperature, the extension of the PEG linker is Q , L 0 is the contour length, and k 0 presents the enthalpic correction. Referring to the literature, , the persistence L p is 3.8 ± 0.02 Å, and k 0 is 1561 ± 33 pN.…”

“…Figure displays that the displacement ( D ) of CD transporting includes the bending distance of the AFM tip cantilever ( d ) and the stretching length of the PEG linker ( Q ), as expressed by the following equation. According to the relationship between PEG stretching behavior and the force, the value of Q could be obtained by the extended worm-like chain (WLC) model: Where L p is the persistence length, k B stands for the Boltzmann constant, T refers to the absolute temperature, the extension of the PEG linker is Q , L 0 is the contour length, and k 0 presents the enthalpic correction. Referring to the literature, , the persistence L p is 3.8 ± 0.02 Å, and k 0 is 1561 ± 33 pN. Contour length L 0 of the PEG linker we used is calculated as 324.45 Å = (PEG unit (4.2 Å) x 76 unit) + 5.25 Å (the length of terminus group).…”

“…Where L p is the persistence length, k B stands for the Boltzmann constant, 30 T refers to the absolute temperature, the extension of the PEG linker is Q, L 0 is the contour length, 31 and k 0 presents the enthalpic correction. Referring to the literature, 29,32 the persistence L p is 3.8 ± 0.02 Å, and k 0 is 1561 ± 33 pN. Contour length L 0 of the PEG linker we used is calculated as 324.45 Å = (PEG unit (4.2 Å) x 76 unit) + 5.25 Å (the length of terminus group).…”