Quaternization enhances the transgene expression efficacy of aminoglycoside-derived polymers

Miryala, Bhavani; Feng, Yunpeng; Omer, Ala; Potta, Thrimoorthy; Rege, Kaushal

doi:10.1016/j.ijpharm.2015.04.026

Cited by 13 publications

(14 citation statements)

References 52 publications

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“…We therefore investigated the role of an organic modifier (isopropyl alcohol) in the eluent in addition to elevated salt concentrations (Grandhi et al, ). Isopropyl alcohol enhances the elution of plasmid DNA from modified Amikabeads and is routinely used in buffers employed in commercially available kits used for pDNA purification (Grandhi et al, ; Miryala, Feng, Omer, Potta, & Rege, ; Potta et al, ; Rege, Hu, Moore, Dordick, & Cramer, ). We, therefore, investigated isopropyl alcohol as an organic phase modifier for modulating the recovery of pDNA from Amikaliths.…”

Section: Resultsmentioning

confidence: 99%

Parallel fabrication of macroporous scaffolds

Dobos

Grandhi

Godeshala

et al. 2018

Biotech & Bioengineering

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Scaffolds generated from naturally occurring and synthetic polymers have been investigated in several applications because of their biocompatibility and tunable chemo-mechanical properties. Existing methods for generation of 3D polymeric scaffolds typically cannot be parallelized, suffer from low throughputs, and do not allow for quick and easy removal of the fragile structures that are formed. Current molds used in hydrogel and scaffold fabrication using solvent casting and porogen leaching are often single-use and do not facilitate 3D scaffold formation in parallel. Here, we describe a simple device and related approaches for the parallel fabrication of macroporous scaffolds. This approach was employed for the generation of macroporous and non-macroporous materials in parallel, in higher throughput and allowed for easy retrieval of these 3D scaffolds once formed. In addition, macroporous scaffolds with interconnected as well as non-interconnected pores were generated, and the versatility of this approach was employed for the generation of 3D scaffolds from diverse materials including an aminoglycoside-derived cationic hydrogel ("Amikagel"), poly(lactic-co-glycolic acid) or PLGA, and collagen. Macroporous scaffolds generated using the device were investigated for plasmid DNA binding and cell loading, indicating the use of this approach for developing materials for different applications in biotechnology. Our results demonstrate that the device-based approach is a simple technology for generating scaffolds in parallel, which can enhance the toolbox of current fabrication techniques.

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Section: Resultsmentioning

confidence: 99%

Parallel fabrication of macroporous scaffolds

Dobos

Grandhi

Godeshala

et al. 2018

Biotech & Bioengineering

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“…Since the aminoglycosides have already been approved by FDA, researchers have further incorporated modifications to enable them to carry genetic therapeutics inside the cells effectively and exhibit high levels of transgene expression. [33][34][35][36][37] Besides, these carriers also offer an added advantage of taking care of any infection during immunity compromising treatment of patients. Most of the aminoglycosides possess abundant hydroxyl and amino functionalities attached to sugar moieties which are amenable to modification/derivatization.…”

Section: Resultsmentioning

confidence: 99%

Bifunctionally engineered polyethylenimines as efficient DNA carriers and antibacterials against resistant pathogens

et al. 2018

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In this study, we have designed and developed two series of bifunctional conjugates by tethering polyethylenimine with streptomycin. By varying the amount of streptomycin, conjugates, polyethylenimine-streptomycin, have been synthesized and characterized spectroscopically. Gel electrophoresis assay revealed a slight decrease in the cationic charge density on the conjugates as these retarded the mobility of pDNA at higher w/w ratios. Further, transfection studies showed that both the series of conjugates transfected the mammalian cells efficiently with low-molecular weight polyethylenimine-streptomycin conjugates were more competent (∼9-fold enhancement with respect to native bPEI) exhibiting high cell viability too. Besides, both the series of conjugates displayed excellent antibacterial activity on pathogenic bacteria, even better than native streptomycin on resistant strains. Altogether, these results ensure the promising potential of the projected bifunctional conjugates as safe and efficient gene delivery vectors as well as antibacterials for future biomedical applications.

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“…In addition, folate‐targeted therapeutics have been investigated in clinical trials, which indicates the translational promise of this strategy . We have previously demonstrated that aminoglycoside‐derived polymers and lipopolymers demonstrated effective levels of transgene expression . Although aminoglycoside antibiotics can be nephrotoxic in their monomeric form, it is not clear if polymers derived from aminoglycosides demonstrate this activity.…”

Section: Discussionmentioning

confidence: 99%

“…66 We have previously demonstrated that aminoglycoside-derived polymers and lipopolymers demonstrated effective levels of transgene expression. [36][37][38] Although aminoglycoside antibiotics can be nephrotoxic in their monomeric form, it is not clear if polymers derived from aminoglycosides demonstrate this activity. Given the high efficacy of these polymers, we hypothesized that conjugating ligands that can bind receptors on cancer cells can lead to targeted delivery vehicles.…”

Section: Discussionmentioning

confidence: 99%

“…Given their chemical diversity, we employed aminoglycosides as starting materials for the generation of bioseparation ligands, DNA‐binding ligands, and microbeads . Recently, we employed parallel synthesis and chemical informatics modeling for the generation and rapid identification of aminoglycoside‐derived polymers and lipopolymers for delivering transgenes to cancer cells . These studies have led to the identification of polymers and lipopolymers that demonstrate higher efficacies for transgene expression than commonly used reagents (e.g., branched pEI).…”

Section: Introductionmentioning

confidence: 99%

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Folate receptor‐targeted aminoglycoside‐derived polymers for transgene expression in cancer cells

Godeshala

Nitiyanandan

Thompson

et al. 2016

Bioengineering & Transla Med

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Targeted delivery of anticancer therapeutics can potentially overcome the limitations associated with current chemotherapeutic regimens. Folate receptors are overexpressed in several cancers, including ovarian, triple‐negative breast and bladder cancers, making them attractive for targeted delivery of nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid‐conjugated, aminoglycoside‐derived polymers for targeted delivery of transgenes to breast and bladder cancer cell lines. Transgene expression was significantly higher with FA‐conjugated aminoglycoside‐derived polymers than with Lipofectamine, and these polymers demonstrated minimal cytotoxicty. Competitive inhibition using free folic acid significantly reduced transgene expression efficacy of folate‐targeted polymers, suggesting a role for folate receptor‐mediated uptake. High efficacy FA‐targeted polymers were employed to deliver a plasmid expressing the TRAIL protein, which induced death in cancer cells. These results indicate that FA‐conjugated aminoglycoside‐derived polymers are promising for targeted delivery of nucleic acids to cancer cells that overexpress folate receptors.

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Quaternization enhances the transgene expression efficacy of aminoglycoside-derived polymers

Cited by 13 publications

References 52 publications

Parallel fabrication of macroporous scaffolds

Parallel fabrication of macroporous scaffolds

Bifunctionally engineered polyethylenimines as efficient DNA carriers and antibacterials against resistant pathogens

Folate receptor‐targeted aminoglycoside‐derived polymers for transgene expression in cancer cells

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