Overcoming the barriers of nuclear-targeted drug delivery using nanomedicine-based strategies for enhanced anticancer therapy

Targeted drug delivery is critical for improving the therapeutic benefits of anticancer drugs. The active delivery strategy increases the bioavailability of drugs not only to the diseased tissue and subsequent individual target cells but also to the active sites inside the target organelles where drugs carry out their desired pharmacological activities. This is particularly important because each anticancer drug has its own action mechanism, and the distribution of the drugs to that intracellular organelle is a prerequisite for their efficient pharmacological effects. Many drugs act within the nucleus; therefore, effective penetration and delivery of nuclear-acting drugs across the biological barriers and finally to the nucleus are critical. Nevertheless, the complex cellular environment with its numerous interactions impedes this process. Particularly, the nuclear-targeting drugs possess inefficient intracellular trafficking and insufficient permeability through the nuclear membrane and are incompetent in targeting the nucleus, resulting in limited pharmacological activity, precluding their desired anticancer therapy. This entire mechanism of delivery of nuclear-acting drugs can be envisaged via mathematical approaches to design nuclear drug delivery systems and optimize the limiting factors that govern the entire mechanism. In this regard, mathematical explanations can play a pivotal role in fully elucidating the drug-host interaction by unifying the biological perspective of cellular biology pathways, the chemical interaction of the crowded environment of the cytoplasm, and the physical aspects of diffusion. Mathematical modeling focuses on understanding the residence time of nanomedicine inside the endosome, the endosomal escape time, the mean activation time, and the respective association-dissociation kinetics. For enhanced efficiency of drug delivery to the nucleus, mathematical approaches incorporating the natural transport system of the cell have been developed. This article highlights the barriers that specifically hurdle the nuclear targeting efficiency of drugs and suggests mathematical approaches to enhance drug penetration and accumulation inside the nucleus to achieve better therapeutic benefits for anticancer therapy.