Overcoming the Low-Stability Bottleneck in the Clinical Translation of Liposomal Pressurized Metered-Dose Inhalers: A Shell Stabilization Strategy Inspired by Biomineralization
Abstract
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].
Part of Table 2. Liposome products on the market, reproduced from He et al. [17] with permission from the Asian Journal of Pharmaceutical Sciences. (click to enlarge)
According to Table 2, liposomes are currently, predominantly utilized in clinical analgesic, anti-fungal therapy, anti-bacterial therapy, and anti-tumor therapy. Liposomes hold immense potential for the treatment of diverse diseases.
1.2. Realistic Needs and Advantages of Liposome Pulmonary Delivery
It is established that liposomes can serve as versatile drug delivery systems for the management of multiple diseases. Currently, the threat of respiratory diseases to global public health cannot be ignored. Approximately 4 million people worldwide die from chronic respiratory diseases, which exhibits extremely high morbidity and mortality [18,19,20]. Of the five major respiratory diseases classified by the International Respiratory Society Forum, chronic obstructive pulmonary disease (COPD) affects approximately 65 million individuals globally and results in 3 million deaths annually, making it the third leading cause of death worldwide. Pneumonia and tuberculosis are among the most common and lethal infectious diseases, causing millions of deaths each year. Around 14% of children worldwide have asthma [21,22,23]. Lung cancer has a five-year survival rate of less than 19% [24]. The clinical demand to treat respiratory diseases is quite urgent globally. In response to this demand, pharmaceutical scientists began exploring the feasibility of using liposomes for the pulmonary delivery of corresponding therapeutic agents.
For the well-known liposome products listed in Table 2, the most common route of administration is injection, either intramuscularly or subcutaneously [25,26]. However, this method of drug delivery has some drawbacks, such as the invasive needle puncture being risky to occupational exposure for medical personnel and low patient compliance during long-term treatment [27]. Pulmonary administration is a non-invasive route that can improve patient compliance. The large surface area of alveolar epithelial cells (>100 m2) [28] enables rapid absorption by the target tissue, leading to fast action. Additionally, this route delivers the therapeutics directly to the respiratory lesion site, bypassing the first-pass effect in the liver and intestine [29]. The lower enzyme activity in the respiratory tract allows drug accumulation without the need for large doses, resulting in fewer side effects and safer treatment [30]. Noticeably, phospholipids, the main components of liposomes, are also the major ingredients of endogenous pulmonary surfactants. Therefore, liposome pulmonary delivery will possess high biocompatibility and a long retention time compared to the lung region [31]. These advantages are significant over injection administration.
Based on the mentioned advantages, in recent years, a large number of fundamental studies and clinical trials regarding liposomes for pulmonary delivery have been performed [32], elucidating that it is a burgeoning field.
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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
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