Overcoming the Low-Stability Bottleneck in the Clinical Translation of Liposomal Pressurized Metered-Dose Inhalers: A Shell Stabilization Strategy Inspired by Biomineralization

Currently, several types of inhalable liposomes have been developed. Among them, liposomal pressurized metered-dose inhalers (pMDIs) have gained much attention due to their cost-effectiveness, patient compliance, and accurate dosages. However, the clinical application of liposomal pMDIs has been hindered by the low stability, i.e., the tendency of the aggregation of the liposome lipid bilayer in hydrophobic propellant medium and brittleness under high mechanical forces. Biomineralization is an evolutionary mechanism that organisms use to resist harsh external environments in nature, providing mechanical support and protection effects. Inspired by such a concept, this paper proposes a shell stabilization strategy (SSS) to solve the problem of the low stability of liposomal pMDIs. Depending on the shell material used, the SSS can be classified into biomineralization (biomineralized using calcium, silicon, manganese, titanium, gadolinium, etc.) biomineralization-like (composite with protein), and layer-by-layer (LbL) assembly (multiple shells structured with diverse materials). This work evaluated the potential of this strategy by reviewing studies on the formation of shells deposited on liposomes or similar structures. It also covered useful synthesis strategies and active molecules/functional groups for modification. We aimed to put forward new insights to promote the stability of liposomal pMDIs and shed some light on the clinical translation of relevant products.

Introduction

1.1. Liposomes Act as Superior Drug Delivery Systems

Nanoparticles are highly dispersed supramolecular structures, typically consisting of polymers, with submicron dimensions that are preferably less than 500 nm [1]. Nanoscale materials have wide applications in various fields, including chemistry [2], biology [3], environment [4], and medicine [5], because they possess physical and chemical properties superior to those of bulk materials. Nanoparticles have become a promising drug delivery platform, due to their abilities to improve the stability and solubility of encapsulated goods, promote transmembrane transport, prolong circulation time, enhance safety and efficacy, and overcome the challenges of traditional delivery with untargeted biological distribution [6]. Many nanoparticle-based medicines, or nanomedicines, have been approved by the FDA, like inorganic, polymeric, and lipid-based medicines (Table 1) [7]. The global nanomedicine market was estimated at USD 53 billion in 2009 and was expected to reach USD 100 billion with a booming growth rate of 13.5% [8].

Table 1. FDA-approved nanomedicines reproduced from Mitchell et al. [7] with permission from the Asian Journal of Pharmaceutical Sciences. (click to enlarge)

Lipid-based nanoparticles are the most commonly used FDA-approved nanomedicines [9], as shown in Table 1. Outstandingly, liposomes are one of the most widely used lipid-based nanoparticles as a drug delivery platform [10,11].

Liposomes are micro–nano systems composed of phospholipid and sterol, constructing one or more concentric circular bilayers [12]. The lipids self-assemble by bringing their polar head groups toward the aqueous phase and positioning their hydrophobic parts in opposite directions into a double layer, forming a closed vesicle with an aqueous core and a lipid bilayer as a wall [13]. The unique structure of liposomes enables them to effectively encapsulate hydrophilic, hydrophobic, and amphiphilic molecules or even smaller nanoparticles. Lipophilic drugs can be encapsulated in the lipid bilayer or adsorbed on the surfaces of liposomes, due to hydrophobic interactions, while hydrophilic drugs can be encapsulated in the aqueous interior of the vesicles [14] (Figure 1).

As a promising carrier, liposomes can contribute to a sustained release of the cargo drug and an improved therapeutic index due to their exceptional targeted delivery, rapid cellular uptake, biodegradability, and potential functionalization [15,16]. After years of research and development, several liposome-based products have been approved, including “star products” Doxil (doxorubicin hydrochloride liposome injection), DepoDur (morphine sulfate sustained-release liposome injection), and AmBisome (amphotericin B liposome dry powder for injection) (Table 2) [17].

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Huang, Y.; Chang, Z.; Gao, Y.; Ren, C.; Lin, Y.; Zhang, X.; Wu, C.; Pan, X.; Huang, Z. Overcoming the Low-Stability Bottleneck in the Clinical Translation of Liposomal Pressurized Metered-Dose Inhalers: A Shell Stabilization Strategy Inspired by Biomineralization. Int. J. Mol. Sci. 2024, 25, 3261. https://doi.org/10.3390/ijms25063261