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Role of Cellular Retention and Intracellular State in Controlling Gene Delivery Efficiency of Multiple Nonviral Carriers.

ABSTRACT: Nonviral gene delivery has seen major progress in the last two decades owing to facile synthesis, low toxicity, and ease of modification of nanocarriers that take nucleic acids to cells and tissues. Gene delivery nanocomplexes need to reach the target locations in significant amounts by overcoming multiple barriers. While the importance of nanocomplex stability, cellular uptake, intracellular trafficking, and nuclear localization has been studied extensively, the role of cellular retention and recycling of these nanocomplexes is less understood in the context of gene delivery. In this study, we used different DNA carriers and made efforts to understand the role played by cellular retention in determining their gene delivery efficiency across multiple cell lines. In addition, we also analyzed whether state of complexation and localization of the nanocomplexes play a role in conjunction with cellular retention. We observed higher transfection efficiencies for nanocomplexes showing better retention, lower unpackaging, and low recycling. Our data also suggests that nanocomplexes made of peptides with terminal cysteine modification show enhanced retention and transfection efficiency compared to their counterparts with no terminal cysteine. Overall, the work highlights myriad of factors to be considered for improving gene delivery efficiency of nanocomplexes.

SUBMITTER: Dahiya UR

PROVIDER: S-EPMC6906788 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Role of Cellular Retention and Intracellular State in Controlling Gene Delivery Efficiency of Multiple Nonviral Carriers.

Dahiya Ujjwal Ranjan UR Mishra Sarita S Chattopadhyay Sabyasachi S Kumari Anupama A Gangal Apurva A Ganguli Munia M

ACS omega 20191126 24

Nonviral gene delivery has seen major progress in the last two decades owing to facile synthesis, low toxicity, and ease of modification of nanocarriers that take nucleic acids to cells and tissues. Gene delivery nanocomplexes need to reach the target locations in significant amounts by overcoming multiple barriers. While the importance of nanocomplex stability, cellular uptake, intracellular trafficking, and nuclear localization has been studied extensively, the role of cellular retention and r ...[more]

PMID: 31858039

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Project description:Lignin is a natural renewable biomass resource with great potential for applications, while its development into high value-added molecules or materials is rare. The development of biomass lignin as potential nonviral gene delivery carriers was initiated by our group through the "grafting-from" approach. Firstly, the lignin was modified into macroinitiator using 2-bromoisobutyryl bromide. Then cationic polymer chains of poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) were grown from the lignin backbone using atom transfer radical polymerization (ATRP) to yield lignin-PDMAEMA graft copolymers (LPs) with branched structure. To gain a deep understanding of the relationship between the nonviral gene transfection efficiency of such copolymers and their structural and compositional factors, herein eight lignin-based macroinitiators with different modification degrees (MDs, from 3.0 to 100%) were synthesized. Initiated by them, a series of 20 LPs were synthesized with varied structural factors such as grafting degree (GD, which is equal to MD, determining the cationic chain number per lignin macromolecule), cationic chain length (represented by number of repeating DMAEMA units per grafted arm or degree of polymerization, DP) as well as the content of N element (N%) which is due to the grafted PDMAEMA chains and proportional to molecular weight of the LPs. The in vitro gene transfection capability of these graft copolymers was evaluated by luciferase assay in HeLa, COS7 and MDA-MB-231cell lines. Generally, the copolymers LP-12 (N% = 7.28, MD = 36.7%, DP = 13.6) and LP-14 (N% = 6.05, MD = 44.4%, DP = 5.5) showed good gene transfection capabilities in the cell lines tested. Overall, the performance of LP-12 was the best among all the LPs in the three cell lines at the N/P ratios from 10 to 30, which was usually several times higher than PEI standard. However, in MDA-MB-231 at N/P ratio of 30, LP-14 showed the best gene transfection performance among all the LPs. Its gene transfection efficiency was ca. 11 times higher than PEI standard at this N/P ratio. This work demonstrated that, although the content of N element (N%) which is due to the grafted PDMAEMA chains primarily determines the gene transfection efficiency of the LPs, it is not the only factor in explaining the performance of such copolymers with the branched structure. Structural factors of these copolymers such as grafting degree and cationic chain length could have a profound effect on the copolymer performance on gene transfection efficiency. Through carefully adjusting these factors, the gene transfection efficiency of the LPs could be modulated and optimized for different cell lines, which could make this new type of biomass-based biomaterial an attractive choice for various gene delivery applications.

Dataset Information

Role of Cellular Retention and Intracellular State in Controlling Gene Delivery Efficiency of Multiple Nonviral Carriers.

Publications

Role of Cellular Retention and Intracellular State in Controlling Gene Delivery Efficiency of Multiple Nonviral Carriers.

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