Evolution of Nanomedicine Formulations for Targeted Delivery and Controlled Release

Abstract

Nanotechnology research over the past several decades has been aimed primarily at improving the physicochemical properties of small molecules to produce druggable candidates as well as for tumor targeting of cytotoxic molecules. The recent focus on genomic medicine and the success of lipid nanoparticles for mRNA vaccines have provided additional impetus for the development of nanoparticle drug carriers for nucleic acid delivery, including siRNA, mRNA, DNA, and oligonucleotides, to create therapeutics that can modulate protein deregulation. Bioassays and characterizations, including trafficking assays, stability, and endosomal escape, are key to understanding the properties of these novel nanomedicine formats. We review historical nanomedicine platforms, characterization methodologies, challenges to their clinical translation, and key quality attributes for commercial translation with a view to their developability into a genomic medicine. New nanoparticle systems for immune targeting, as well as in vivo gene editing and in situ CAR therapy, are also highlighted as emerging areas.

Introduction

Nanotechnology took center stage in materials research in the 1970s because of its utility to improve the solubility of compounds for oral and parenteral administration. This achievement was followed by an increasing focus on the potential of nanoparticles as carriers for drugs targeting tumor tissues [1]. Both active and passive targeting by nanoparticles have been explored for decades as new possibilities have arisen for creating novel materials. The promising potential of nanoparticle containing drug molecules are due to their pharmacokinetic properties, such as modified clearance, retention, and half-life, useful attributes for molecules with an efficacy profile based on the area under the curve (AUC) or maximum concentration (C_max) (quick onset). Table 1 summarizes the predominant classes of nanoparticle systems reported in the descriptive literature.

Nanotherapeutics can potentially reduce systemic toxicity and improve the therapeutic index of pharmaceuticals. Nanoparticle conjugates containing peptides or small-molecule ligands can serve as actively targeted systems with the ability to better traffic cargo to the tissue of interest. Actively targeted nanoparticles can benefit from the interaction of targeting ligands with cell surface receptors, leading to receptor-mediated endocytosis [2] and internalization of the cargo into cells. This property of cellular uptake and trafficking can potentially enable nanoparticle-containing cargos to deliver messenger RNAs (mRNAs) to the cytoplasm and DNA to the nucleus.

In addition to these important attributes, nanoparticle systems can provide controlled release of a drug payload. This feature is important in drug delivery, particularly for drugs with a narrow therapeutic index, as well as for reducing dosing frequency and improving patient acceptance. Building controlled-release capabilities into nanoparticles can achieve either quick release, via C_max-driven efficacy, or slow release, via AUC extension, with varying kinetics of release and concentration gradients to support longer release and desired plasma levels.

Nanoparticle-based drug delivery systems for tumor targeting has been a theme of research for the past three decades. Extensive research has led to nanotechnology applications focusing on tumor targeting, including factors that can influence systemic delivery to tumors and overcome the physiological barriers that are intrinsic to the tumor microenvironment [3]. To address these tumor-related challenges, investigators have recently studied nanocarriers and their unique interactions with immune cells as efficient tools for the enhancement of tumor regression [3], [4], [5], [6], [7]. Targeted immunotherapy can potentially overcome the heterogeneity of cancer cells as well as the immune suppression developed by the tumor and the tumor microenvironment. In the immune targeting approach, nanoparticles can potentially impact the immune cascade and induce an antitumor response by enhancing immunostimulatory signals. This response can be generated through various mechanisms via activation of antigen-presenting cells and T cells. In this regard, as an emerging area of science, nanoparticles are now being evaluated for the purpose of targeting immune cells, such as macrophages and monocytes [8], [9], [10], [11], [12], [13], [14], [15], as opposed to tumor cells.

Several researchers have looked at targeting cancers through influencing the immune system [9], [10], [11], [13], [14]. Min et al. [16] reported engineered antigen-capturing nanoparticles that are bound by a series of protein antigens based on the surface properties of the nanoparticle. Their study demonstrated that antigen-capturing nanoparticles can deliver tumor-specific proteins to antigen-presenting cells and further improve the efficacy of treatment with anti-programmed cell death protein 1 in a B16F10 melanoma model by induction of CD8⁺ cytotoxic T cells and enhanced CD4⁺ and CD8⁺ T-cell ratios. Nguyen et al. [17] reported a dual-scale mesoporous silica-based cancer vaccine consisting of mesoporous silica microrods coupled with mesoporous silica nanoparticles. In that study, the nanoparticles were co-loaded with an antigen and Toll-like receptor 9 agonist that was located in the interparticle spaces of the scaffold of the mesoporous silica microrods. Internalization of nanoparticles by the recruited dendritic cells ultimately generated antigen-specific T cells and inhibited melanoma growth. More recently, Carreira et al. [18] highlighted the role of nanomedicines as multifunctional modulators of the melanoma immune microenvironment. These authors found that nano-based systems could simultaneously allow the modulation of specific immune cells while controlling the delivery of molecular agents. This observation captures the controlled-release function of nanoparticle delivery with simultaneous engagement of immune cells.

For nanoparticles to be considered as candidates for immune targeting, their physicochemical and material science properties must be engineered to target the immune system. Fig. 1 shows a five-point methodology design wheel that can be used to influence the engineering of nanoparticles so that they can better interact with the immune system. In addition to the standard physicochemical parameters of nanoparticles, such as charge, size, shape, protein corona, and composition, elasticity of the particles is an important parameter that can impact blood circulation, targeting capabilities, and endocytosis. Elastic modulus is a measure of flexibility of the particles, and it has been shown that optimizing particle elasticity can facilitate the biodistribution of nanoparticles, affecting circulation time, immune system uptake, and targeting [19].

Genomic medicine is a scientific discipline involving the use of individual patients’ genomic information to tailor diagnosis and treatment. In recent decades, the field has made a significant departure from small-molecule and biologic therapeutics to achieve important advancements in the development of medications with nucleic acids such as DNA, xRNA, and antisense oligonucleotides. The success of these advancements depends on the development of drug delivery systems that can deliver the nucleic acid cargo intracellularly with great precision and without systemic side effects. In this review, we discuss the utility of nanoparticles for nucleic acid delivery and immune targeting, the various types of nanoparticles and how they have evolved as dosage forms, key contributors to success, and some of the translational challenges that have yet to be addressed.