Stimuli-responsive nanocarriers capable of minimizing the systemic toxicity associated with most free anticancer drugs have attracted extensive attention in modern chemotherapy. We report here a DNA and DNase based formulation for enhanced anticancer delivery. This bio-inspired drug delivery system consists of a DNA nanoclew weaved by long chain single stranded DNA and an acid degradable polymeric nanocapsule with DNase I caged inside (Figure 1). The DNA nanoclew was synthesized by rolling circle amplification (RCA) with its surface negatively charged and doxorubicin (DOX) was loaded into the DNA core by intercalating into the GC-base pair sequences (DOX/NCl). The polymeric nanogel containing positively charged monomers was cross-linked onto DNase I surface by acid degradable cross-linkers, which made the DNase I nanocapsule (NCa) positively charged as well as acid degradable. NCa was embedded into NCl <i>via</i> electrostatic interaction and formed a cocoon like structure with NCl as the “cocoon matrix” and NCa as “hibernating worms”. The NCa was stable in physiological conditions while degraded in acid environment and exposed the encapsulated DNase I to its substrate DOX/NCl, promoting release of DOX (Figure 1). To further enhance the targetability of DOX/NCl/NCa, folic acid (FA) was conjugated to a DNA oligo complementary to NCl form DOX/FA-NCl/NCa. Rapid DOX/FA-NCl/NCa internalization and nucleus targeting in breast cancer cell line MCF 7 that overexpressed folate receptors was observed within 0.5 h. Embedding NCo into NCl reduced the half-maximal inhibitory concentration (IC<sub>50</sub>) of DOX from 2.3 μM in DOX/NCl to 1.2 μM in DOX/NCl/NCa, which was further reduced to 0.9 μM after the conjugation of folic acid.

Bio-inspired cocoon-like DNA-nanoclew for anticancer drug delivery

249th National Meeting (2015)

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