Poly(ethylene glycol)-block-cationic polylactide nanocomplexes of differing charge density for gene delivery

Chen, Chih‐Kuang; Jones, Charles H.; Mistriotis, Panagiotis; Yu, Yun; Ma, Xiaoni; Ravikrishnan, Anitha; Jiang, Ming; Andreadis, Stelios T.; Pfeifer, Blaine A.; Cheng, Chong

doi:10.1016/j.biomaterials.2013.08.063

Cited by 74 publications

(82 citation statements)

References 63 publications

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“…Of particular interest, cationic polymers (CP) represent a viable gene delivery option due to their notable design plasticity, low cytotoxicity, and effective delivery outcomes. [3][4][5][6] Within this set of vectors, poly(beta-amino esters) (PBAEs) have been used extensively in the successful delivery of various genetic cargo in both in vitro and in vivo applications. 7-10 Current gene delivery research has predominately focused on engineering criteria towards optimal uptake and processing that is applicable for all cell types.…”

Section: Introductionmentioning

confidence: 99%

Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery

et al. 2015

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Antigen presenting cell (APC) gene delivery is a promising avenue for modulating immunological outcomes toward a desired state. Recently, our group developed a delivery methodology to elicit targeted and elevated levels of APC-mediated gene delivery. During these initial studies, we observed APC-specific structure-function relationships with the vectors used during gene delivery that differ from current non-APC cell lines, thus, emphasizing a need to re-evaluate vector-associated parameters in the context of APC gene transfer. Thus, we describe the synthesis and characterization of a second-generation mannosylated poly(β-amino ester) library stratified by molecular weight. To better understand the APC-specific structure-function relationships governing polymeric gene delivery, the library was systematically characterized by (1) polymer molecular weight, (2) relative mannose content, (3) polyplex biophysical properties, and (4) gene delivery efficacy. In this library, polymers with the lowest molecular weight and highest relative mannose content possessed gene delivery transfection efficiencies as good as or better than commercial controls. Among this group, the most effective polymers formed the smallest polymer-plasmid DNA complexes (∼300 nm) with moderate charge densities (<10 mV). This convergence in polymer structure and polyplex biophysical properties suggests a unique mode of action and provides a framework within which future APC-targeting polymers can be designed.

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Section: Introductionmentioning

confidence: 99%

Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery

et al. 2015

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“…However, complications associated with complex biomaterial synthetic schemes, associated polymer cytotoxicity, incomplete ligand conjugation, and the costs associate with attaching biological targeting molecules (such as antibodies) must be addressed for eventual application. Cationic polymers are commonly used as nucleic acid complexation agents for the purpose of gene delivery[28–33]. In particular, the poly(beta-amino ester) (PBAE) family of polymers has garnered attention for simple synthetic schemes, ease of functionalization, and safe degradation profiles[28–30].…”

Section: Introductionmentioning

confidence: 99%

Mannosylated poly(beta-amino esters) for targeted antigen presenting cell immune modulation

et al. 2015

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Given the rise of antibiotic resistance and other difficult-to-treat diseases, genetic vaccination is a promising preventative approach that can be tailored and scaled according to the vector chosen for gene delivery. However, most vectors currently utilized rely on ubiquitous delivery mechanisms that ineffectively target important immune effectors such as antigen presenting cells (APCs). As such, APC targeting allows the option for tuning the direction (humoral vs cell-mediated) and strength of the resulting immune responses. In this work, we present the development and assessment of a library of mannosylated poly(beta-amino esters) (PBAEs) that represent a new class of easily synthesized APC-targeting cationic polymers. Polymeric characterization and assessment methodologies were designed to provide a more realistic physiochemical profile prior to in vivo evaluation. Gene delivery assessment in vitro showed significant improvement upon PBAE mannosylation and suggested that mannose-mediated uptake and processing influence the magnitude of gene delivery. Furthermore, mannosylated PBAEs demonstrated a strong, efficient, and safe in vivo humoral immune response without use of adjuvants when compared to genetic and protein control antigens. In summary, the gene delivery effectiveness provided by mannosylated PBAE vectors offers specificity and potency in directing APC activation and subsequent immune responses.

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“…Cationic polymers can be designed as various architectures, such as linear, graft (comb), branched, and dendritic, which influence complexation and delivery capabilities of the polymer vehicle. 7–12 Novel synthetic approaches allow integration of many features needed for gene therapy into one macromolecular delivery system, including functionality to prevent immunogenicity, 13 recognize cell surfaces, 14,15 and localize to the nucleus. 16–18 …”

Section: Introductionmentioning

confidence: 99%

Polymer–Peptide Delivery Platforms: Effect of Oligopeptide Orientation on Polymer-Based DNA Delivery

et al. 2014

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The success of non-viral transfection using polymers hinges on efficient nuclear uptake of nucleic acid cargo and overcoming intra- and extracellular barriers. By incorporating PKKKRKV heptapeptide pendent groups as nuclear localization signals (NLS) on a polymer backbone, we demonstrate protein expression levels higher than obtained from JetPEI™ and Lipofectamine™ 2000, the latter being notorious for coupling high transfection efficiency with cytotoxicity. The orientation of the NLS peptide grafts markedly affected transfection performance. Polymers with the sequence attached to the backbone from the valine residue achieved higher nuclear translocation relative to those having the NLS groups attached in the opposite orientation. The differences in nuclear localization and DNA complexation strength between the two orientations correlated with a striking difference in protein expression, both in cell culture and in vivo. Polyplexes formed from these comb polymer structures exhibited transfection efficiencies superior to those of Lipofectamine 2000 but with greatly reduced toxicity. Moreover, these novel polymers enabled high reporter gene expression in mice when administered by intramuscular ultrasound-mediated delivery, demonstrating their therapeutic promise in vivo.

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Poly(ethylene glycol)-block-cationic polylactide nanocomplexes of differing charge density for gene delivery

Cited by 74 publications

References 63 publications

Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery

Structure–Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery

Mannosylated poly(beta-amino esters) for targeted antigen presenting cell immune modulation

Polymer–Peptide Delivery Platforms: Effect of Oligopeptide Orientation on Polymer-Based DNA Delivery

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