The Role of Inhaled Chitosan-Based Nanoparticles in Lung Cancer Therapy

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to the limited efficacy of anticancer drugs, which is primarily attributed to insufficient doses reaching the lungs. Additionally, patients undergoing treatment experience severe systemic adverse effects due to the distribution of anticancer drugs to non-targeted sites. In light of these challenges, there has been a growing interest in pulmonary administration of drugs for the treatment of lung cancer. This route allows drugs to be delivered directly to the lungs, resulting in high local concentrations that can enhance antitumor efficacy while mitigating systemic toxic effects. However, pulmonary administration poses the challenge of overcoming the mechanical, chemical, and immunological defenses of the respiratory tract that prevent the inhaled drug from properly penetrating the lungs. To overcome these drawbacks, the use of nanoparticles in inhaler formulations may be a promising strategy. Nanoparticles can assist in minimizing drug clearance, increasing penetration into the lung epithelium, and enhancing cellular uptake. They can also facilitate increased drug stability, promote controlled drug release, and delivery to target sites, such as the tumor environment. Among them, chitosan-based nanoparticles demonstrate advantages over other polymeric nanocarriers due to their unique biological properties, including antitumor activity and mucoadhesive capacity. These properties have the potential to enhance the efficacy of the drug when administered via the pulmonary route. In view of the above, this paper provides an overview of the research conducted on the delivery of anticancer drug-loaded chitosan-based nanoparticles incorporated into inhaled drug delivery devices for the treatment of lung cancer. Furthermore, the article addresses the use of emerging technologies, such as siRNA (small interfering RNA), in the context of lung cancer therapy. Particularly, recent studies employing chitosan-based nanoparticles for siRNA delivery via the pulmonary route are described.

Keywords: anticancer drugs; chitosan; lung cancer; nanoparticles; pulmonary drug delivery; siRNA.

Figure 1

Anatomy of the human respiratory system.

Figure 2

The major physiological barriers involved in the delivery of therapeutic agents to the lungs. The image shows the cellular and non-cellular barriers involved in the process of administering therapeutic agents via the pulmonary route.

Figure 3

Representation of the chitin deacetylation process for the formation of CS. Chitin is subjected to a treatment process in which it is immersed in a concentrated solution of sodium hydroxide (NaOH) at high temperatures for a prolonged period of time. This treatment process results in the formation of CS as an insoluble by-product.

Figure 4

(A) The IC50 values in the WISH and A549 cell lines demonstrated that the LP5 formulation significantly amplified the anticancer effects of RES by 63.2-fold. (B) In addition, LP5 treatment demonstrated higher anticancer selectivity index values (5.511) in A549 cells in comparison to those of doxorubicin (0.878). Reproduced with permission from [23]; published by Elsevier, 2022.

Figure 5

The schematic illustrates the steps involved in the cellular uptake and delivery of siRNA into the lungs. In order for the nanoparticles to be released into the cytoplasm of lung cells, they must escape from the endocytic vesicle. Consequently, during the process of endocytosis, the nanoparticles are localized within the endosome. As the endosome matures, the acidification process occurs, resulting in a pH of 5–6. During the acidification of the endosomes, the primary amines present in CS are progressively protonated, resulting in an influx of chloride ions into the endosomes to maintain charge neutrality and increase the ionic strength in the endosomes. This process results in osmotic swelling and the physical rupture of the endosome, thereby releasing the siRNA into the cytoplasm. Subsequently, the siRNAs associate with the RNA-induced silencing complex (RISC), a large protein complex comprising Argonaut (Ago2) proteins. When bound to RISC, the siRNA unwinds and the sense strand is removed and degraded by nucleases. The antisense strand of the siRNA directs RISC to the target mRNA. The cleavage site is aligned with the Ago2 endonuclease domain, which facilitates cleavage of the phosphodiester bond in the mRNA and the subsequent release of the cleaved mRNA fragments, which are then degraded, resulting in gene silencing.

Figure 6

The biodistribution test demonstrated that pulmonary administration of non-encapsulated siRNA led to rapid dispersion from the lung tissue into the systemic circulation. Conversely, the translocation of siRNA from the lung to the systemic circulation and liver was delayed when both the Cy5.5-siRNA/chitosan solution (SL) and the Cy5.5-siRNA/chitosan powder (DP) were administered. This indicates that chitosan prolonged siRNA retention in the lungs. Reproduced with permission from [166]; published by J-STAGE, 2013.