The most exciting phrase to hear in science, the one that heralds new discoveries,
is not 'Eureka!' (I found it!) but 'That's funny ...' - Isaac Asimov (1920 - 1992)
Systemic delivery of nucleic acids
Gene therapeutics overcome the limitations of traditional small molecule drugs (limited “druggable” targets) and protein drugs (size, stability). Due to the diverse functions of genes in living organisms, they are expected to address numerous diseases that have not been effectively treated with existing therapeutics. In particular, RNA therapeutics have gained significant interest in recent years as they circumvent the need for entering cell nuclei, which accounts for the safety concerns of DNA drugs. RNA therapeutics come in different forms and sizes, such as antisense oligonucleotides, aptamers, small interfering RNAs (siRNA), microRNAs, and messenger RNA (mRNA), playing diverse roles in disease progression. If they can be delivered to target sites safely and effectively, RNA therapeutics will dramatically change the landscape of pharmaceutical industry. The challenge is, and has always been, the effective delivery of RNA therapeutics. The existing RNA delivery strategies, albeit effective in vaccine delivery and local therapies, have fundamental limitations in treating diseases of extrahepatic organs due to the dependence of carriers on charge-based interactions with RNA. Moreover, the current carriers require cold chain storage, limiting their global distribution and use, as seen with mRNA vaccines. We have recently reported Nanosac, a non-cationic, flexible polyphenol-based nanocarrier, which overcomes the main limitations of existing RNA carriers. We are developing Nanosac for the systemic delivery of a broad range of RNA therapeutics in applications requiring extrahepatic delivery.
More than a century ago, Dr. William Coley injected a cocktail of inactivated bacteria, now known as Coley’s toxin, to a patient with an inoperable tumor and saw tumor regression in a few days. Scientists have since come to understand that the antitumor activity of Coley’s toxin is likely attributable to bacterial DNA with CpG motifs, which stimulated the patient’s immune system to attack the tumor. The idea of stimulating local immune responses to suppress tumor growth is now prevailing and actively tested with a better-defined form of pathogen-associated molecular patterns. Drug delivery systems have played a significant role in local immunotherapy by controlling the spatiotemporal presentation of the immunostimulatory molecules and reducing their side effects. We are developing new drug carriers for the delivery of immunostimulatory agents and immunogenic cell death inducers to leverage the host immune system, thereby activating anti-tumor immunity to protect cancer patients from recurrent diseases and metastasis.
We are also working to develop drug delivery systems for systemic therapy of sepsis, severe systemic inflammatory responses to infection, which can lead to fatal consequences. Current sepsis treatments focus on early infections and support end-organ functions. Several experimental approaches have also been undertaken to address various aspects of sepsis conditions. However, they do not always improve patient outcomes, as evidenced by persistent sepsis mortality. We are interested in using polymyxin B (PMB), which is well suited for sepsis therapy due to the endotoxin affinity and antibacterial activity but is difficult to use systemically due to the dose-limiting toxicity. We have reported a nanoparticle form of PMB, which selectively reduces its toxicity to mammalian cells but retains the therapeutic activities. The PMB-nanoparticles protect animals challenged with pre-established endotoxemia and polymicrobial sepsis, showing no systemic toxicities inherent to PMB. We are working to streamline the production of PMB-nanoparticles for clinical development.
Nanoparticles for anticancer drug delivery
In developing safe and effective chemotherapy, it is essential to engineer a targeted drug delivery system that can selectively deliver antiproliferative drugs to tumor cells without affecting normal cells. While extensive efforts are made to enhance the recognition of drug carriers by tumor tissues, the targeting effect mostly depends on the imperfect vasculature of tumors, which leads to preferential extravasation of drug carriers. This limitation in the current targeting strategy is partly due to the diversity and heterogeneity of the tumor cells. It may also be related to the endothelium surrounding tumors, which limits drug carriers from accessing the underlying tissues. Another challenge in tumor-targeted drug delivery is that many drug carriers are not stable in blood. The instability of drug carriers leads to premature release of the entrapped drugs during circulation.
We are addressing these challenges in three ways. One approach is to develop a nanocarrier system that remains inert without releasing drugs in normal tissues but changes into a cell-interactive form by common features of the tumor microenvironment such as pH or overexpressed enzymes. We have developed a new biocompatible chitosan derivative, which shows zwitterionic charge profiles like proteins. We have demonstrated that the chitosan derivative serves as a conditional stealth coating material for nanocarriers, which prevents random interaction of the carriers with normal tissues or serum proteins but allows high-affinity interactions with cells in the acidic environment of hypoxic tumors. The other approach is to engineer a nanocarrier surface to enhance its extravasation at tumor tissues. To this end, NPs are decorated with a quinic acid derivative, a small molecule mimic of E-selectin that binds to sialyl Lewis-x on the endothelium surrounding tumors, via a simple surface modification method based on polyphenols. Another approach is to produce drug nanocrystals with high lattice energy, which remain stable in circulation for a prolonged period without leaching out free drugs until they reach tumors. The nanocrystals are coated with intact albumin to protect them from the reticuloendothelial system and improve their interactions with tumor tissues via albumin-receptor-mediated interactions.
Long-acting drug delivery systems
One of the ultimate goals of controlled drug delivery is to maintain an effective plasma drug concentration for the desired period by providing a constant and extended supply of a drug. These products help reduce the frequency of administration and adverse effects related to drug level fluctuation, thus improving the effectiveness of therapy and the experience of patients. The development of long-acting drug delivery products requires flexible control of drug release kinetics according to the application. We are developing strategies to control drug release kinetics for different applications, ranging from post-surgical analgesia to chronic ocular disease therapy, which requires sustained and constant drug release anywhere between a few weeks to months.