1. Introduction

Lung cancer is the most frequently diagnosed cancer in the world and a common reason for cancer-related deaths ^[1]. For patients diagnosed with this type of cancer, the 5-year survival rate is approximately 17.8%^[2]. Lung cancer can be divided into three main subtypes according to microscopic evidence and histological profiles: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and lung carcinoid tumor, accounting for 85%, 10–15%, and less than 5% of cases, respectively^[3]. Among the three subtypes of lung cancer, NSCLC is the most common one diagnosed in non-smokers. It appears in women more than men, and it is more frequently discovered in younger people than other type of lung cancer^[4]. This type can be subdivided, according to World Health Organization (WHO), into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma^[5].

Adenocarcinoma is a popular type, representing around 40% of all total diagnostic cases. It usually occurs in smokers and nonsmokers^[6]. It arises from small airway epithelial cells that form the lining of the lung and alveolar cells: the mucus secreting cells^[7]. Furthermore, it grows slowly and can spread outside the lungs. Adenocarcinoma is characterized histologically by the presence of glandular/acinar growth, papillar differentiation, or a single-layer of wallpaper-like spread along the alveolar septum and bronchioles^[8]. Squamous-cell carcinoma is derived from the squamous cell type located at the airways of the epithelial cells. These cells line the bronchial tubes in the center of the lungs. This type is mostly associated with smoking tobacco, and it represents 30% of all lung cancer patients^[9]. It is histologically identified by the presence of keratinization or intercellular bridges.

Large cell carcinoma comprises 5–10% of lung cancer patients. It arises from the central region of the lungs, the area nearest to the lymph nodes, and the wall of the chest^[10]. It usually grows and spreads rapidly, which makes its treatment challenging. Large cell carcinoma, also called non–small cell cancer, has a poor prognosis^[11].

SCLC represents 25% of all invasive cancer types worldwide, and it is found exclusively in smokers^[12]. It originates from neuroendocrine cell precursors. Thus, it is attributed to endocrine and neurologic paraneoplastic syndromes (Eaton Lambert syndrome, inappropriate antidiuretic hormone secretion, and Cushing’s syndrome)^[12]. Moreover, it is characterized by its worse clinical course than that of NSCLC^[13][14]. Additionally, it can be resistant to both chemotherapy and radiotherapy courses^[15][16].

The last type of lung cancer is lung carcinoid tumor. It originates from neuroendocrine cells, which is are special cells located in the lungs. The growth of this type of cancer is typically very slow and it rarely spreads (see Figure 1)^[17].

Figure 1. Schematic diagram illustrating different types of lung cancer (non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and lung carcinoid tumors, as well as non-small cell lung cancer).

Here, we try to highlight the development and application of nanoparticles in lung cancer treatment, mainly those made of liposomes, lipids, and polymer materials. Many nanoparticle-based therapies have been developed for the treatment of metastatic NSCLC, such as liposomes, polymeric nanoparticles (NPs), albumin NPs, Lipid NPs, inorganic NPs, and metal NPs. However, few have been translated successfully into clinical trials. In our current study, liposomes, solid lipid nanoparticles (SLNPs), polymeric nanoparticles (PNPs), and hybrid polymeric materials were studied, and they are summarized in Table 1, Table 2 and Table 3, while the successful nanoparticles that moved into clinical trials are outlined in Table 4.

2. Clinical Studies of Pulmonary Nanoparticles Can Be Finally Driven into the Industry Market

Clinical trials represent strategy-based scientific research that attempts to evaluate the influence of a new therapeutic molecule on human health outcomes. It includes several steps, as follows: Phase I—the study of new therapeutic molecules on a small group of volunteers; Phase II—monitoring and evaluation of safe drugs on a large group of volunteers; Phase III—the study of safe drugs in different groups of volunteers located in different regions and countries; and Phase IV—monitoring of safe drugs after obtaining approval for their use in a wide population over long time frame^[18]. During the clinical trial process, each drug is given a particular description according to its status, as summarized in Table 4. For instance, it is “recruiting” when several participants are invited to contribute to the study, while “active” status means the study is underway. On the other hand, when the investigation is finished, there is no need for any participants. The status of the drug is changed to “completed”. “Terminated” status means that the study has stopped and will not be started again^[19]. In the current review, we have described the use of several nanochemotherapeutic agents to treat lung cancer, and recently, they have reached clinical trial status. Irinotecan liposome injection has obtained a “recurring” status and is being investigated in comparison with topotecan in patients with small cell lung cancer after treatment with a platinum-based first-line therapy (Phase 3; 2018–2022 study). Many studies have completed the clinical study process, such as Cholesterol-Fus1 in non-small-cell lung cancer^[20] and the liposomal form of Lurtotecan as OSI-211 to treat recurrent small cell lung cancer^[21]. Stimulating Targeted Antigenic Responses To NSCLC (START) was a phase III trial of the MUC1-antigen-specific cancer immunotherapy tecemotide, following chemoradiotherapy for unresectable stage III NSCLC^[22] and a liposomal formed of Lurtotecan [7(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20-(S)-camptothecin dihydrochloride] was combined with cisplatin to treat patients with advanced or metastatic solid tumors. A phase II trial of this combination showed that three of 25 patients with breast cancer and two of 23 patients with NSCLC had partial responses^[23].