The advantages and critical aspects of nanodimensional polymer-coated viral vector systems potentially applicable for gene delivery are reviewed. Various viral and nonviral vectors have been explored for gene therapy. Viral gene transfer methods, although highly efficient, are limited by their immunogenicity. Nonviral vectors have a lower transfection efficiency as a result of their inability to escape from the endosome. To overcome these drawbacks, novel nanotechnology-mediated interventions that involve the coating or modification of virus using polymers have emerged as a new paradigm in gene therapy. These alterations not only modify the tropism of the virus, but also reduce their undesirable interactions with the biological system. Also, co-encapsulation of other therapeutic agents in the polymeric coating may serve to augment the treatment efficacy. The viral particles can aid endosomal escape, as well as nuclear targeting, thereby enhancing the transfection efficiency. The integration of the desirable properties of both viral and nonviral vectors has been found beneficial for gene therapy by enhancing the transduction efficiency and minimizing the immune response. However, it is essential to ensure that these attempts should not compromise on the inherent ability of viruses to target and internalize into the cells and escape the endosomes.

Polyketals are a class of acid-responsive polymers that have been relatively less explored for drug delivery applications compared to polyesters. The degradation of these polymers is accelerated in an acidic medium and does not result in acidic byproducts. Their biocompatibility depends on the diol used for the synthesis. The present work aims to synthesize, characterize, and fabricate nanospheres of an aliphatic polyketal for delivery of the nucleotide analogue cytarabine toward the treatment of acute myeloid leukemia (AML). The internalization mechanism of the nanospheres was probed, and its implication on the nuclear localization and escape from the endo-lysosomal compartments were studied. The drug-loaded polyketal nanoparticles reduced the cell viability to a greater extent compared with the free drug. The effect of the drug-loaded polyketal nanoparticles on the differential gene expression of leukemic cells was investigated for the first time to understand their therapeutic implications. It was found that treatment with drug-loaded polyketal nanoparticles downregulated AML-specific genes involved in cell proliferation and recurrence compared to the free drug. The protein expression studies were performed for selected genes obtained from gene expression analysis. Biodistribution studies showed that the poly­(cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) nanoparticles exhibit prolonged circulation time. Overall, our results suggest that polyketal-based delivery of cytarabine represents a more effective alternative strategy for AML therapy.

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