Modulating Macrophage Clearance of Nanoparticles: Comparison of Small-Molecule and Biologic Drugs as Pharmacokinetic Modifiers of Soft Nanomaterials.

Nanomedicines show benefits in overcoming the limitations of conventional drug delivery systems by reducing side effects, toxicity, and exhibiting enhanced pharmacokinetic (PK) profiles to improve the therapeutic window of small-molecule drugs. However, upon administration, many nanoparticles (NPs) prompt induction of host innate immune responses, which in combination with other clearance pathways such as renal and hepatic, eliminate up to 99% of the administered dose. Here, we explore a drug predosing strategy to transiently suppress the mononuclear phagocyte system (MPS), subsequently improving the PK profile and biological behaviors exhibited by a model NP system [hyperbranched polymers (HBPs)] in an immunocompetent mouse model. In vitro assays allowed the identification of five drug candidates that attenuated cellular association. Predosing of lead compounds chloroquine (CQ) and zoledronic acid (ZA) further showed increased HBP retention within the circulatory system of mice, as shown by both fluorescence imaging and positron emission tomography-computed tomography. Flow cytometric evaluation of spleen and liver tissue cells following intravenous administration further demonstrated that CQ and ZA significantly reduced HBP association with myeloid cells by 23 and 16%, respectively. The results of this study support the use of CQ to pharmacologically suppress the MPS to improve NP PKs.

Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation.

For decades, nanomedicines have been reported as a potential means to overcome the limitations of conventional drug delivery systems by reducing side effects, toxicity and the non-ideal pharmacokinetic behaviour typically exhibited by small molecule drugs. However, upon administration many nanoparticles prompt induction of host inflammatory responses due to recognition and uptake by macrophages, eliminating up to 95% of the administered dose. While significant advances in nanoparticle engineering and consequent therapeutic efficacy have been made, it is becoming clear that nanoparticle recognition by the mononuclear phagocyte system (MPS) poses an impassable junction in the current framework of nanoparticle development. Hence, this has negative consequences on the clinical translation of nanotechnology with respect to therapeutic efficacy, systemic toxicity and economic benefit. In order to improve the translation of nanomedicines from bench-to-bedside, there is a requirement to either modify nanomedicines in terms of how they interact with intrinsic processes in the body, or modulate the body to be more accommodating for nanomedicine treatments. Here we provide an overview of the current standard for design elements of nanoparticles, as well as factors to consider when producing nanomedicines that have minimal MPS-nanoparticle interactions; we explore this landscape across the cellular to tissue and organ levels. Further, rather than designing materials to suit the body, a growing research niche involves modulating biological responses to administered nanomaterials. We here discuss how developing strategic methods of MPS 'pre-conditioning' with small molecule or biological drugs, as well as implementing strategic dosing regimens, such as 'decoy' nanoparticles, is essential to increasing nanoparticle therapeutic efficacy. By adopting such a perspective, we hope to highlight the increasing trends in research dedicated to improving nanomedicine translation, and subsequently making a positive clinical impact.