Alkyl-Modified Oligonucleotides as Intercalating Vehicles for Doxorubicin Uptake via Albumin Binding

Abstract

DNA-based drug delivery vehicles have displayed promise for the delivery of intercalating drugs. Here, we demonstrate that oligonucleotides modified with an alkyl chain can bind to human serum albumin, mimicking the natural binding of fatty acids. These alkyl-DNA-albumin complexes display excellent serum stability and are capable of strongly binding doxorubicin. Complexes are internalized by cells in vitro, trafficking to the mitochondria, and are capable of delivering doxorubicin with excellent efficiency resulting in cell death. However, the cellular localization of the delivered doxorubicin, and ultimately the complex efficacy, is dependent on the nature of the linker between the alkyl group and the oligonucleotide.

Dumbbell-Shaped Antisense Oligonucleotide Prodrugs Showed Improved Antinuclease Stability and Anticancer Efficacy

“…Nevertheless, L2 was a little more stable than L4; the reason might be the alkyl chain in the loop domain of L2 being less susceptible to nuclease than the nucleotide-containing loop in L4. In addition, as indicated by Purdie et al, oligonucleotides modified by an alkyl chain within the hairpin may couple to human serum albumin, thus providing prominent serum stability . A surface plasmon resonance assay indicated that L2 with alkyl chains did show interaction with human serum albumin (KD = 5.222 × 10 –7 mol/L), while native L1 did not (Figure S1).…”

“…In addition, as indicated by Purdie et al, oligonucleotides modified by an alkyl chain within the hairpin may couple to human serum albumin, thus providing prominent serum stability. 21 A surface plasmon resonance assay indicated that L2 with alkyl chains did show interaction with human serum albumin (KD = 5.222 × 10 −7 mol/L), while native L1 did not (Figure S1).…”

Protein-Based Systems for Topical Antibacterial Therapy

“…The triggered release behavior of albumin nanoparticles ( 103 ) can be potentially utilized for the on-demand antibacterial release upon application to infected wounds. Furthermore, albumin coatings on nanoparticles can facilitate the targeting and trafficking during drug delivery ( 104 ). Similar strategies can be used for topical application of albumin coated nanoparticles to facilitate uptake inside the cells infected with bacteria for the induction of antibacterial effects.…”

Dendritic amphiphilic siRNA: Selective albumin binding, in vivo efficacy, and low toxicity

“…However, the precise design of these lipidic/hydrophobic conjugates is essential, as they can also result in binding to other proteins in circulation. 19 , 20 Multiple studies have reported that changes in the design of conjugates intended to bind albumin, drastically impact their affinity and active delivery in vitro . 19 , 21 Hence, strong, selective, and carefully designed albumin-binding moieties are attractive modalities to append to nucleic acid therapeutics.…”