We describe the combinatorial synthesis and cheminformatics modeling of aminoglycoside antibiotics-derived polymers for transgene delivery and expression. Fifty-six polymers were synthesized by polymerizing aminoglycosides with diglycidyl ether cross-linkers. Parallel screening resulted in identification of several lead polymers that resulted in high transgene expression levels in cells. The role of polymer physicochemical properties in determining efficacy of transgene expression was investigated using Quantitative Structure-Activity Relationship (QSAR) cheminformatics models based on Support Vector Regression (SVR) and ‘building block’ polymer structures. The QSAR model exhibited high predictive ability, and investigation of descriptors in the model, using molecular visualization and correlation plots, indicated that physicochemical attributes related to both, aminoglycosides and diglycidyl ethers facilitated transgene expression. This work synergistically combines combinatorial synthesis and parallel screening with cheminformatics-based QSAR models for discovery and physicochemical elucidation of effective antibiotics-derived polymers for transgene delivery in medicine and biotechnology.

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Photo-cross-linkable, functionalized, and thermosensitive polyphosphazenes were synthesized to develop a dual cross-linking system with properties of mechanically suitable strength and controllable biodegradation for injectable biomedical applications. The aqueous solutions of the polymers exhibited sol-gel transition behaviors against temperature. The incorporated methacrylate groups were photo-cross-linked upon UV light under mild conditions, which resulted in the formation of compact three-dimensional networks. The thermoresponsive hydrophobic interactions at body temperature facilitated the rapid dual cross-linking accomplishment of the photo-cross-linking even under mild conditions. The characteristics of the polymers such as pore size and density showed that the inner three-dimensional networks depended on the degree of cross-linking of methacrylate units. Mechanical properties of the gel were also improved several folds after developing the photo-cross-linking in the network from the in vivo degradation studies. The results demonstrate that the photo-cross-linkable and thermoresponsive polyphosphazenes have great potential as injectable, biodegradable, and controllable carriers for various biomedical applications by tuning the mechanical gel property and the degradation rate.

We describe the parallel synthesis of lipopolymers generated by conjugating alkanoyl chlorides to polymers derived from aminoglycoside antibiotic monomers as novel vehicles for transgene delivery and expression in mammalian cells. Parallel screening of lipopolymers led to the identification of six leads that demonstrated higher transgene expression efficacies in several cancer cells, when compared to the parental polymers as well as 25 kDa poly(ethylene imine), a current standard for polymer-mediated transgene expression. Quantitiative structure− activity relationship (QSAR)-based cheminformatics modeling was employed in order to investigate the role of lipopolymer physicochemical properties (molecular descriptors) on transgene expression efficacy. The predictive ability of the QSAR model, investgated using lipopolymers not employed for training the model, demonstrated excellent agreement with experimentally observed transgene expression. Our findings indicate that lipid substitution on aminoglycoside-derived polymers results in high levels of transgene expression compared to unsubstituted polymers. Taken together, these materials show significant promise in nonviral transgene delivery with several applications in biotechnology and medicine.

A focused library of twenty-one cationic poly(amino ethers) was synthesized following ring-opening polymerization of two diglycidyl ethers by different oligoamines. The polymers were screened in parallel for plasmid DNA (pDNA) delivery, and transgene expression efficacies of individual polymers were compared to those of 25 kDa polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Seven lead polymers that demonstrated higher transgene expression than PEI in pancreatic and prostate cancer cells lines were identified from the screen. All seven lead polymers showed highest transgene expression at a polymer:pDNA weight ratio of 5:1 in the MIA PaCa-2 pancreatic cancer cell line. Among the conditions studied, transgene expression efficacy correlated with minimal polymer cytotoxicity but not polyplex sizes. In addition, this study indicated that methylene spacing between amine centers in the monomers, amine content, and molecular weight of the polymers are all significant factors and should be considered when designing polymers for transgene delivery. A lead effective polymer was employed for coating gold nanorods, leading to theranostic nanoassemblies that possess combined transgene delivery and optical imaging capabilities, leading to potential theranostic systems.

Gene therapy is an attractive treatment option for diseases of genetic origin, including several cancers and cardiovascular diseases. While viruses are effective vectors for delivering exogenous genes to cells, concerns related to insertional mutagenesis, immunogenicity, lack of tropism, decay and high production costs necessitate the discovery of non-viral methods. Significant efforts have been focused on cationic polymers as non-viral alternatives for gene delivery. Recent studies have employed combinatorial syntheses and parallel screening methods for enhancing the efficacy of gene delivery, biocompatibility of the delivery vehicle, and overcoming cellular level barriers as they relate to polymer-mediated transgene uptake, transport, transcription, and expression. This review summarizes and discusses recent advances in combinatorial syntheses and parallel screening of cationic polymer libraries for the discovery of efficient and safe gene delivery systems.

Plasmid DNA (pDNA) therapeutics are being investigated for gene therapy and DNA vaccines against diseases including cancer, cystic fibrosis and AIDS. In addition, several applications in modern biotechnology require pDNA for transient protein production. Here, we describe the synthesis, characterization, and evaluation of microbeads ("Amikabeads") derived from the aminoglycoside antibiotic amikacin for pDNA binding and in situ DNA capture from mammalian cells. The parental aminoglycoside-derived microbeads (Amikabeads-P) acted as anion-exchange materials, and demonstrated high capacities for binding pDNA. Binding of pDNA was significantly enhanced following quaternization of the amines on the microbeads (Amikabeads-Q). Amikabeads were further employed for the disruption and extraction of DNA from mammalian cells, indicating their utility for in situ DNA capture. Our results indicate that Amikabeads are a novel material, with multiple reactive groups for further conjugation, and can have several applications in plasmid DNA biotechnology.