Toll-like receptors (TLRs) are a potential target for cancer immunotherapy due to their role in the activation of the innate immune system. More specifically, TLR7/8, two structurally similar pattern recognition receptors that trigger interferon and cytokine responses, have proven to be therapeutically relevant targets for cancer in numerous preclinical and clinical studies. When triggered by an agonist, such as imiquimod or resiquimod, the TLR7/8 activation pathway induces cellular and humoral immune responses that can kill cancer cells with high specificity. Unfortunately, TLR7/8 agonists also present a number of issues that must be overcome prior to broad clinical implementation, such as poor drug solubility and systemic toxic effects. To overcome the key limitations of TLR7/8 agonists as a cancer therapy, biomaterial-based drug delivery systems have been developed. These delivery devices are highly diverse in their design and include systems that can be directly administered to the tumor, passively accumulated in relevant cancerous and lymph tissues, triggered by environmental stimuli, or actively targeted to specific physiological areas and cellular populations. In addition to improved delivery systems, recent studies have also demonstrated the potential benefits of TLR7/8 agonist codelivery with other types of therapies, particularly checkpoint inhibitors, cancer vaccines, and chemotherapeutics, which can yield impressive anti-cancer effects. In this review, we discuss recent advances in the development of TLR7/8 agonist delivery systems and provide perspective on promising future directions.

Despite the success of therapeutics and prophylactics in prolonging life and improving quality of life, these benefits are limited by poor patient adherence, which can be as low as 50% in patients with chronic conditions. [3][4][5] This lack of patient adherence contributes to negative outcomes, including death, and results in an additional $289 billion in healthcare costs each year in the United States alone. [6][7][8] Reducing drug dosing frequency has been identified as one of the most effective means to increase patient adherence. [9,10] However, many diseases including diabetes, cancer, human immunodeficiency virus infection, depression, and autoimmune disorders, are typically treated with frequent, repeated, and longterm administration of therapeutics, often as frequently as multiple times a day, to maintain drug levels that are both safe and effective. Controlled drug delivery systems represent a promising solution to mitigate compliance issues. By releasing drugs over an extended period of time, these systems can be administered less frequently, thereby improving adherence and patient outcomes. For example, the FDA-approved Lupron Depot, composed of drug-loaded biodegradable microspheres, has been shown to improve patient adherence and convenience by reducing administration frequency from a once-daily injection to one injection every one to six months. [11,12] Oral delivery systems are convenient, but their rapid passage through the gastrointestinal tract limits their duration of action, often requiring frequent re-dosing that can lead to lower levels of patient adherence compared to less frequent parenteral injection(s). [13] Unfortunately, most injectable controlled-release systems generate an initial burst release followed by first-order release kinetics in which drug is released at a perpetually lower rate over time. [14,15] Although these devices extend the duration of drug activity, their front-loaded and slowing rate of release limits their ability to maintain therapeutic efficacy over a long period of time, especially when the biological half-life of the drug is short or the therapeutic window is small. Increasing initial drug loading can extend the duration of release in these Pulsatile drug delivery systems have the potential to improve patient adherence and therapeutic efficacy by providing a sequence of doses in a single injection. Herein, a novel platform, termed Particles Uniformly Liquified and Sealed to Encapsulate Drugs (PULSED) is developed, which enables the high-throughput fabrication of microparticles exhibiting pulsatile release. In PULSED, biodegradable polymeric microstructures with an open cavity are formed using high-resolution 3D printing and soft lithography, filled with drug, and sealed using a contactless heating step in which the polymer flows over the orifice to form a complete shell around a drug-loaded core. Poly(lactic-co-glycolic acid) particles with this structure can rapidly release encapsulated material after delays of 10 ± 1, 15 ± 1, 17 ± 2, or 36 ± 1 days in vivo, ...

No abstract