Nanoparticles as Drug Delivery Systems and Applications in Infectious Disease Treatment

A variety of organic and inorganic biomaterials have been developed as delivery systems, from the first liposomal system described in 1965 to more recent systems with virus- or bacteria-like properties (biomimetic systems) or with capabilities of stimulating therapeutic release and action in response to interactions with the surrounding environment. This section of the chapter will review some of the common nanoparticle types and their formulation and describe selected studies in which the nanoparticles were investigated for infectious disease therapy. Due to the broadness of the infectious disease field, the examples provided herein are derived from studies directed towards HIV, ТВ and malaria treatment. Due to the intracellular residence of infectious disease pathogens, the design of nanoparticles should facilitate entry into the intracellular space and potentially including the nucleus (Fig. 12.1).

12.3.1 Liposomes

Liposomes are spherical vesicles consisting of phospholipid bilayers capability to entrap water-soluble drugs in the hydrophilic compartment and hydrophobic drugs in the lipid layers. They therefore present an opportunity to deliver drug cocktails of both hydrophilic and hydrophobic drugs. Drug delivery with liposomes has been widely investigated and has had numerous commercial applications, including in

Schematic diagram illustrating the intracellular locality of M

FIGURE 12.1 Schematic diagram illustrating the intracellular locality of M. tb and HIV pathogens, and the various types of nanoparticles. M. tb is typically contained within phagosomes, while HIV is located within the nucleus. In most cases, nanoparticles will need to penetrate the cellular host/intracellular space and/or nucleus to deliver therapeutic payload.

infectious diseases (Zazo et al., 2016). One such example is AmBisome® (liposomal Amphotericin B), approved by the FDA in 1997 for the treatment of fungal and protozoal infections. Liposomes have also been used to deliver latency activators to CD4+ T cells for the treatment of HIV (Kovochich et al., 2011). Kovochich et al. (2011) reported liposome-based co-delivery of nelfinavir and bryostatin-2 and consequent activation of latent virus and inhibition of virus spread. Mannose-decorated liposomes have been used by Chono et al. (2008) to achieve increased ciprofloxacin levels in macrophages and in plasma. Greco et al. (2012) constructed Janus-faced liposomes for ТВ treatment. The liposomes were constructed with external phospha- tidylserine (induces phagocytic recognition and engulfment) and internal phospha- tidic acid (promotes phagolysosome maturation). These liposomes could be taken up efficiently by macrophages leading to increased intracellular killing of M. tb.

12.3.2 Polymeric Nanoparticles

Biodegradable polymeric particles offer enhanced stability of drugs, biocompatibility with tissues and cells and controlled release of bioactives (Kumari et al., 2010). Various methods of synthesis have been developed leading to polymeric nanoparticles tailor-made according to the need of application and the drug to be encapsulated. Polyesters have been the most studied and well characterized of the synthetic biodegradable polymers and among them poly(e-caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA) and their copolymer poly(lactic acid-co-gly- colic acid) (PLGA) have received great attention due to better encapsulation, better controlled release and less toxicity (Kumari et al., 2010). PLGA has been the most successfully used and has received FDA approval in various drug delivery systems (Danhier et al. 2012). Natural polymers such as alginate, albumin and chitosan have also been used as drug delivery vehicles. Polymeric nanoparticles are typically coated with polyethylene glycol (PEG) to alter their distribution by enhancing their circulation time and increase the delivery of therapeutic molecules. PEG has the capability to minimize recognition of nanoparticles by plasma proteins and avoid uptake by macrophages for clearance (Semete et al., 2010a). Polymeric nanoparticles have been investigated for anti-ТВ and anti-HIV chemotherapy, designed to improve the pharmacokinetic profiles allowing for better dosage schedules to reduce cytotoxicity and side effects (Semete et al., 2010b; Dube et al., 2014; Makita-Chingombe et al., 2016). Early studies established that encapsulation of antitubercular drugs in polymeric nanoparticles could extend plasma concentrations of the drug, and also increase and extend drug residence time in tissue (Sharma et al., 2004; Gelperina et al., 2005; Pandey et al., 2003). Pandey et al. (2003) showed that when anti-ТВ drugs are encapsulated in PLGA nanoparticles and orally administered to mice, the drugs can be detected in plasma and tissues (lung, liver, spleen) for extended periods of time (up to 9-11 days) at concentrations above the required minimum inhibitory concentration. This is in contrast to free drug which was eliminated within 24 hours in plasma and 48 hours in tissue (Pandey et al., 2003). In a study utilizing M. tb infected guinea pigs, Ahmad et al. administered nebulized alginate nanoparticles at three doses that were spaced 15 days apart for 45 days, whereas free drugs were orally administered daily for 45 days. The study reported undetectable mycobacterial colony-forming units in the lungs and the spleen, suggesting the potential of nanoparticles to modify dosing regimens (Zahoor et al., 2005). The Gendelman group at the University of Nebraska has performed extensive studies to develop long-acting antiretrovirals encapsulated in nanoparticles (Gendelman et ah, 2019; Hilaire et ah, 2019; Ibrahim et ah, 2019; Smith et ah, 2019; Soni et ah, 2019; Wang et ah 2020; Lin et ah, 2018; McMillan et ah, 2018; Sillman et ah, 2018; Zhou et ah, 2018; Guo et ah, 2017; Singh et ah, 2016; Edagwa et ah, 2014). For example, a prodrug of lamivudine was encapsulated within polymeric nanoparticles producing a long-acting nanoformulation. Pharmacokinetic studies in rats demonstrated sustained drug levels in blood and tissues for 30 days (Smith et ah, 2019). Recently, there has been a shift from utilizing polymeric nanoparticles to modulate intracellular drug pharmacokinetics (Tukulula et ah, 2018) to utilizing the nanoparticles to also activate the innate immune system, i.e. immunotherapy for infectious diseases (Dube and Reynolds, 2016; Liu et ah, 2016; Bekale et ah; 2018). Dube et ah (2014) synthesized a p-glucan functionalized chitosan-PLGA nanoparticles and demonstrated that these nanoparticles activated macrophages, i.e. resulted in a significant enhancement of reactive oxygen species and proinflammatory cytokines, including TNF-a production, compared to nanoparticles without p-glucan functionalization. This study, and that described by Greco et ah, working with liposomes (Greco et ah, 2012), demonstrates the potential of this immunotherapy approach towards eradication of intracellular pathogens.

12.3.3 Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLN) are colloidal drug delivery systems consisting of a hydrophobic solid lipid core covered with a monolayer of phospholipid coating (zur Miihlen et ah, 1998). A majority of SLNs are prepared by high-pressure homogenization either at temperatures above the melting point of the lipid (hot homogenization) or at cold temperature (cold homogenization) in the presence of a surfactant/stabi- lizer. Hydrophobic drugs are dissolved in the melted lipid during hot homogenization. Hydrophilic drugs are encapsulated using the cold homogenization technique to partitioning between the melted lipid and the water phase during hot homogenization (Muller et ah, 2000). Within the antimicrobial field, the therapeutic potential of anti- TB drug loaded SLNs has been investigated (Pandey and Khuller, 2005). A SLN formulation was demonstrated to improve half-life of the antimalarial tafenoquine, and also mitigate drug toxicity against red blood cells (Melariri et ah, 2015). Lipid-based nanoformulations of the antiretroviral rilpivirine have been shown to be long acting, extending the drug half-life and improving tissue distribution (Hilaire et ah, 2019).

12.3.4 Metallic Nanoparticles

Metallic nanoparticles are generally synthesized by the chemical reduction of a chemical salt (gold - Au, silver - Ag, titanium, platinum) with a reducing agent and their characteristics being modified by control of different synthesis conditions such as temperature, pH, reduction time or reducing agent concentration (Mody et ah, 20Ю). Ag nanoparticles have inherent antimicrobial properties and have found their main therapeutic application in the antimicrobial field (Wei et al., 2015). Au nanoparticles have been used to target antibacterial drugs which were linked to the particles through Au-S or Au-amino bonds (Zhao and Jiang, 2013; Grace and Pandian, 2007). Metallic nanoparticles are also potential antitubercular agents. Spherical Au and Ag nanoparticles were reported to display good antibacterial activity against BCG (Zhou et al., 2012). With regards to HIV, Ag nanoparticles have been shown to exert antiviral action against HIV (Lara et al., 2010). Recently, metal organic framework nanoparticles have been explored for targeted delivery of antitubercular drugs (Guo et al., 2019; Wyszogrodzka et al., 2018). Due to their safety and high drug loading capacity, these particles are promising next-generation drug delivery systems for infectious diseases (Wyszogrodzka et al., 2018). For the treatment of neuro-AIDS, magnetoelectric nanoparticles have been investigated for the delivery of antiretrovirals across the blood-brain barrier. Saiyed et al. (2010) demonstrated the delivery of azidothymidine across the BBB using iron oxide nanoparticle loaded liposomes (Saiyed et al., 2010). Ferric-cobalt nanoparticles were synthesized, having an siRNA bound to the surface to target Beclin-1 and were found to be able to Saiyid cross the BBB and attenuate the neurotoxic effects of HIV-1 infection (Rodriguez et al., 2017). An HIV theranostic comprised of rilpivirine l77lutetium labelled bismuth sulfide nanorods demonstrated potent antiretroviral activities in cell-based assays and was shown to be a viable tool to monitor the distribution and transport of the antiretroviral in a mouse model (Kevadiya et al., 2020).

12.3.5 Calcium Carbonate Particles

In recent times calcium carbonate (CaCO,) has gained increasing attention in drug delivery due to its enhanced biocompatibility and biodegradability in comparison to its counterparts (silica nanoparticles, calcium phosphates, carbon nanotubes, hydroxylapatites). CaCO, can be obtained by precipitation of aqueous calcium and carbonate solutions (liquid-liquid reactions) or carbonation of a calcium solution (gas-liquid reactions) (Zeynep et al., 2015). Increased interest in bioinspired materials and environment-friendly processes has recently led to the formulation of CaCO, particles using supercritical CO, (ScCO,) technology. ScCO, is a highly efficient and versatile approach for the synthesis of CaCO, and offers optimal experimental conditions ideal for sensitive therapeutic compounds (Hassani et al., 2013). CaCO, particles have been studied for the pulmonary delivery of antibiotics to treat lung infections. Moreover, their size (1-5 pm) and their density provides them an excellent mass median aerodynamic diameter, compatible with their local administration as dry powders, a good penetration and retention in the lungs in the presence of airway narrowing (Tewes et al., 2016).

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