The challenges of selective accumulation at the tissue of interest, cellular int

Question

The challenges of selective accumulation at the tissue of interest, cellular internalization and endosomal escape are common to the delivery of all nucleic acid therapeutics. However, DNA delivery must also provide transport into the nucleus to allow access to the transcriptional machinery (FIG. 1). It was reported nearly 30 years ago that direct microinjection of plasmid DNA that encoded thymidine kinase into the nuclei of thymidine kinasedeficient cells resulted in expression of the kinase in 50–100% of the nuclei, as detected by the incorporation of 3 H-thymidine into DNA following autoradiographic analyses39. However, in >1,000 cells that received cytoplasmic injections of the same plasmid DNA, no thymidine kinase activity was detected. The importance of the?nuclear barrier is further highlighted by the observation that quiescent or slowly dividing cells with intact nuclei are generally more difficult to transfect than cells that divide rapidly and that undergo frequent breakdown of their nuclear envelopes40. Both deterministic and stochastic kinetic models of synthetic gene delivery have identified nuclear uptake as a potential rate-limiting step

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Explanation / Answer

Selective accumulation is a process where drugs are uniformly distributed in a specific tissue of intrest. Intact nuclei are the nuclei tagged in specific cell types.

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