Review articleNanocarrier centered therapeutic approaches: Recent developments with insight towards the future in the management of lung cancer
Graphical abstract
Introduction
Lung cancer is the second and third most commonly occurring cancer in men and women, respectively [[1], [2], [3]]. According to the statistics reported by world health organization (WHO), lung cancer was the most commonly occurring cancer worldwide, accounting for 2.1 million new cases and 1.8 million deaths in 2018 [4]. As per the statistics reported by the American Cancer Society, about 228,820 new cases and 135,720 deaths are estimated for lung cancer in the United States in 2020 [2]. Furthermore, 85% of cancer is classified as non-small cell lung cancer (NSCLC), 10%–15% classified as small cell lung cancer (SCLC), and 5% classified as lung carcinoid tumor [5]. As reported by European Union (EU-28), more than 275 thousand people died in 2016 from lung cancer which accounts for 5.4% of the total number of deaths occurred and 19.9% of all deaths from cancer [6]. Recent data demonstrate that lung cancer is the main cause of death among European females than breast cancer [7,8]. It is a situation that causes a cell to divide uncontrollably in the lung and mainly occurs in older age people [9]. Hereditary as well as environmental factors along with exposure to pollutants like asbestos, arsenic, toxins, radon, etc., increase the risk of producing lung tumors. Smoking is also another major risk factor that causes lung cancer [[10], [11], [12], [13]].
Depending upon the type of malevolence and stages of cancer at the time of prognosis, surgery, radiation therapy, and chemotherapy are currently available first-line treatment for both local and non-metastatic cancer [14,15]. However, such first-line treatment fails to control metastatic cancerous tumors that have affected other distant organs. Besides, the use of a chemotherapeutic agent for the inhibition of multiplication of fast-growing cancerous cells undesirably affects the normal/healthy growing cells such as hair follicles, bone marrow, skin, and gastrointestinal tract cells resulting in uneven toxicity [16,17]. The other drawbacks of conventional chemotherapy viz. chances of recurrence, multidrug resistance phenomenon, and improper biodistribution leading to a very low concentration of chemotherapeutic agents reaching the tumor site reduce the therapeutic effect of the anticancer drugs [18,19]. This necessitates finding a new beneficial treatment based on nanocarrier assisted targeted approaches [20] probably through intravenous and inhalable route, that direct anticancer agents to molecular targets/receptors overexpressed on part or surface of cancerous tumor cells [13,21]. The use of nanotechnology in drug delivery has increased the interests of formulation scientists worldwide, due to its ability to alter the drug's pharmacokinetics [22]. Nanotechnology is a new therapeutic platform that utilizes various nanocarriers for the treatment and diagnosis of lung cancer as depicted in Fig. 1 [[23], [24], [25]].
Nanocarriers are defined as nanosized colloidal systems loaded with therapeutic agents (anticancer agents or any macromolecule as proteins or genes) that allow drugs to selectively accumulate in the cancerous tumor site. This provides a several-fold increase in the concentration of drug in tumors with lower toxicity to the rest of body organs as compared to the free drug [21,26]. They are utilized in lung cancer therapy due to their unique nanosized range i.e. 1–1000 nm but preferably within 5–200 nm for drug delivery [24,27]. The particle size in the nanometer scale, surface modification/functionalization, and larger surface to volume ratio plays an important role for in vivo biodistribution [28,29]. Furthermore, nanosized carriers possibly protect the drug or any macromolecules (proteins, peptides, etc.) from degradation, decrease the renal clearance, provide a controlled or sustained release kinetics that increase drug efficacy at a steady-state therapeutic level, increase its half-life in the bloodstream, improve the therapeutic index, solubility, and stability of encapsulated agents than conventional therapies like tablets, capsules, and injection. In nutshell, it completely changes the pharmacokinetic profile of encapsulated agents [30,31]. The review aspires to highlight various traits of nanocarriers that would be valuable in designing novel drug delivery systems taking advantage of the latest developments in nanomedical skills critical to lung cancer.
Section snippets
Passive and active targeting approach of nanocarriers
Passive targeting is a form of tumor-targeting which derives its application based on the enhanced permeability of the endothelium of blood vessels in tumor than in the normal healthy condition. Since, conditions like inflammation/hypoxia are emblematic of tumors, hastily growing tumors engage new vessels or surround existing blood vessels. These freshly generated leaky vessels permit selectively enhanced permeation of nanosystems to the tumor stroma and further, their retention is boosted in
Endocytosis of nanocarrier
Endocytosis is a process that allows a nanocarrier present in the external environment of cells to interact with the plasma membrane/cell membrane providing access inside the cell. It can be allocated into two wide categories namely phagocytosis and pinocytosis or in other words uptake of larger particles and uptake of fluids/solutes, respectively [52,53]. Phagocytosis is a process by which macrophages engulf particles as bigger as 20 μm [54]. This process involves dedicated phagocytes such as
Overexpressed receptors
Various types of cell surface receptors, explained below, are overexpressed in lung cancer cells as compared to normal healthy cells. By targeting those receptors via a specific type of ligand, may improve the therapeutic efficacy of nanocarriers loaded chemotherapeutic agents.
Nanocarriers
Drug nanocarriers embodying liposomes, polymer-drug conjugates, polymersomes, nanoparticles, micelles, dendrimers, carbon nanotubes and nanofibres are nanosized supramolecular structures (diameter 1–100 nm) that give extra protection to loaded or attached anticancer agents over conventional drug therapy. Also, its acceptability is currently increased due to controlled drug release behavior and increased in vivo performance of encapsulated agents [27,29,162,163]. Presently, various types of
Inhalable nano-drug delivery systems
Inhalation therapy locally delivers therapeutic agents to target tissues yielding an increase in its therapeutic efficacy and reducing the toxicity of the anticancer agents as compared to systemic delivery. Additionally, being a needle-free delivery also eliminates the first-pass metabolism and enhances the patient's comfort to treatment [293]. One of the first clinical studies involving the pulmonary inhalable administration of a 5- fluorouracil (5-FU) solution through nebulized aerosols in
Nano-imaging platform as diagnostic tools for lung cancer
The current footprints of progress in nanotechnology are providing exciting potentials for biomedical imaging specifically for cancers [323]. Particles at a nano-level scale display distinctive physical and chemical characteristic that permits the construction of diagnostic probes resulting in improved signal intensity, better contrast, amplification, quantification, and improved distribution [324]. Thus, nanotechnology has emerged as a revolutionary field in oncology, governing the usage of
Formulation challenges and physicochemical characteristics
Nanocarriers are likely to be three-dimensional fabricate of various components with desired spatial arrangements for their functions. As a consequence, minor variations in process or composition can badly affect the complex superposition of the components with negative end-results. As discussed in each nanocarriers section, multiple obstacles exist before it can move to the clinic, starting with the successful manufacture of this complex fabricates and complete characterization. Formulation of
Future perspectives
Although the progression of nanocarriers has been reflected as a promising approach for lung cancer therapy, still they cannot be considered impeccable owing to various unmet needs for their successful delivery. First of all, inadequate drug release from nanocarriers can result in drug resistance. However, approaches encompassing advanced multifunctional targeted nanocarriers for tumor selectivity, endosomal disturbance for instant drug release in the cytoplasm as well as delivering combination
Conclusion
The field of nanotechnology partakes newly fostered approaches for lung cancer therapy. Various types of nanocarriers studied in this field have allowed researchers to overcome the limitations of conventional therapy, by increasing the targeting efficiency through active and passive approaches as well as decreasing the distribution and associated toxicity to healthy tissues. Targeting approaches employing overexpressed receptors can boost the outcomes in the management of lung carcinoma. The
Declaration of competing interest
The authors confirm that this article content has no conflict of interest.
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