Inorganic nanoparticles for oral drug delivery: opportunities, barriers, and future perspectives

Abstract

Oral delivery is the preferred route of drug administration due to patient compliance and convenience. Despite this, nanomedicines have so far primarily been developed for the parenteral route. Inorganic nanoparticles hold great promise as theranostics for oral drug delivery. This is gaining importance especially for the local treatment of gastrointestinal (GI) diseases. However, successful oral delivery of inorganic nanoparticles is challenged by complex physiological conditions in the GI tract. We discuss the main GI barriers and their impact on nanoparticle biotransformation and toxicity. An improved understanding of the complex interplay of inorganic nanoparticles with the dynamic GI environment can facilitate the development of efficient oral nanomedicines.

Introduction

Nanomedicine has been an active area of research since the discovery of liposomes in the 1960s [1]. Nanotechnology in medicine and pharmaceutical research has aided great discoveries in the treatment, imaging, and diagnosis of various conditions, especially in oncology 2, 3. Today, more than 30 types of nanoparticles have been approved in the clinic. The Food and Drug Administration (FDA) approval of lipid nanoparticle-based carriers for the mRNA vaccines against COVID-19 has fueled even greater interest in nanomedicine [4]. In fact, parenterally administered lipid nanoparticles make up the largest fraction of clinically approved nanoparticles, followed by inorganic nanoparticles as the second largest group. The latter are primarily iron oxide-based nanoparticles used in the systemic treatment of iron-deficient anemia and kidney disease [5•].

Compared with systemically administered nanoparticles, orally administered ones have been much less studied, despite the oral route being the most common (approx. 60% of approved drug products) and showing best patient compliance. Nevertheless, orally administered inorganic nanoparticles are well-established as food additives, for example, in the form of SiO₂ (E551), a common and generally-regarded-as-safe food additive [6]. Furthermore, the successful clinical translation of systemically administered nanomedicines, offer promising pharmaceutical and biomedical applications of inorganic nanoparticles in the gastrointestinal tract (GIT). Orally administered inorganic nanoparticles can be used i) as carriers for systemic drug absorption, ii) for local treatment of gastrointestinal (GI) diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), and iii) for imaging applications. Thus, the function of orally administered nanoparticles does not solely rely on their translocation across the intestinal epithelium. However, oral administration of inorganic nanoparticles is challenging due to multiple barriers presented by the GIT. These include its high enzymatic activity, variations in pH, the intestinal mucosal barrier, and absorption across the intestinal epithelium. The functionality and fate of inorganic nanoparticles in the GIT depend on their physicochemical properties such as composition, size, shape, porosity, and surface chemistry (Figure 1).

Inorganic nanoparticles are most often explored for their theranostic potential, that is, combined diagnosis and treatment. This level of functionality is difficult to achieve with lipid-based or polymeric nanoparticles. The most commonly used inorganic nanoparticles for biomedical applications include pure metals (especially plasmonic nanoparticles such as Au and Ag), metal oxides (e.g. solid or mesoporous SiO₂, γ-Fe₂O₃/Fe₃O₄), semiconductor materials (quantum dots), and calcium phosphates. Gold nanoparticles are extensively studied due to their high biocompatibility, ease of synthesis, and bioconjugation, as well as tunable optical and thermal properties. The latter properties make gold nanoparticles of particular interest for photothermal therapy (PTT), in which near-infrared (NIR) light is used to trigger localized hyperthermia. Iron oxide nanoparticles have also been widely studied for hyperthermia, magnetically targeted drug-delivery applications, and as contrast agents in magnetic resonance imaging. Recently, hybrid materials have been developed that combine the benefits of several nanoparticle classes [7]. For the interested reader, there are detailed reviews covering the synthesis, physicochemical properties, and biomedical applications of the most commonly used inorganic nanomaterials: gold [8], silver [9], iron oxide 10, 11, titanium dioxide [12], and silica dioxide 13, 14.

Here, we review recent advances in orally administered inorganic nanoparticles for disease treatment and diagnosis. First, we highlight the barriers encountered by nanoparticles in the GIT and how these impact their dissolution, aggregation, and biodistribution. We focus specifically on the interplay between the GI environment and the nanoparticles themselves. The interested reader is referred to recently published reviews on drug solubility [15], dissolution [16], and ultimately absorption [17] from the GIT. We emphasize the importance of developing in vitro methods that more closely mimic the dynamic physiological conditions encountered by nanoparticles in the GIT. A special focus is placed on the emerging use of oral inorganic nanoparticles as theranostics for GI diseases. Finally, we address toxicity issues related to nanoparticles and their impact on the successful clinical translation of oral inorganic nanomedicines.

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Shno Asad, Ann-Christin Jacobsen, Alexandra Teleki, Inorganic nanoparticles for oral drug delivery: opportunities, barriers, and future perspectives, Current Opinion in Chemical Engineering, Volume 38, 2022, 100869, ISSN 2211-3398,
https://doi.org/10.1016/j.coche.2022.100869.