Review article
Nanocarrier centered therapeutic approaches: Recent developments with insight towards the future in the management of lung cancer

https://doi.org/10.1016/j.jddst.2020.102070Get rights and content

Abstract

At present, drug delivery strategies for minimizing unwanted toxicity to healthy cells and improving the therapeutic efficacy have gained greater momentum, especially for lung cancer diagnosis and chemotherapy. Advances in material sciences have provided novel nanoscale active and passive targeting strategies that provide a new hope to lung cancer suffering patients. Various types of nanocarriers have already been approved for medical use, while many are under preclinical as well as clinical investigations. Nanocarrier based drug delivery is an emerging modality for the treatment of dreadful lung cancer as it offers enhanced bioavailability by improving the pharmacokinetics of a poorly water-soluble drug, in vivo stability, better solubility, greater safety as well as sustained and controlled targeted drug delivery. It bestows the targeting potential than conventional drug delivery on account of selective accumulation of innovative nanocarriers in the tumor site. To date, various types of nanocarriers have been investigated against lung cancer that comprises of liposomes, polymer-drug conjugates, polymersomes, nanoparticles, micelles, dendrimers, carbon nanotubes, and nanofibres. Thus, this review aims to provide an overview of several types of receptors overexpressed in lung cancer and focused therapeutic involvement of nanosized carriers as targeting/developing tools for the treatment of lung cancer. It also provides insights into the formulation challenges and physicochemical characteristics of nanocarriers affecting it's in vitro and in vivo performance. The nanocarrier based novel imaging platforms are also emphasized as a diagnostic means in the management of lung cancer.

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.

References (336)

  • P. Couvreur

    Nanoparticles in drug delivery: past, present and future

    Adv. Drug Deliv. Rev.

    (2013)
  • N. Bertrand et al.

    Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology

    Adv. Drug Deliv. Rev.

    (2014)
  • Y. Malam et al.

    Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer

    Trends Pharmacol. Sci.

    (2009)
  • F. Danhier et al.

    Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles

  • N. Marasini et al.

    Polymer-drug conjugates as inhalable drug delivery systems: a review

    Curr. Opin. Colloid Interface Sci.

    (2017)
  • X.Y. Lu et al.

    Polymer nanoparticles

  • Y. Javadzadeh et al.

    Therapeutic nanostructures for pulmonary drug delivery

  • G. Sahay et al.

    Endocytosis of nanomedicines

    J. Contr. Release

    (2010)
  • T.G. Iversen et al.

    Endocytosis and intracellular transport of nanoparticles: present knowledge and need for future studies

    Nano Today

    (2011)
  • H. Costa Verdera et al.

    Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis

    J. Contr. Release

    (2017)
  • O. Harush-Frenkel et al.

    Targeting of nanoparticles to the clathrin-mediated endocytic pathway

    Biochem. Biophys. Res. Commun.

    (2007)
  • J.K. Vasir et al.

    Quantification of the force of nanoparticle-cell membrane interactions and its influence on intracellular trafficking of nanoparticles

    Biomaterials

    (2008)
  • Y. Lu et al.

    Folate-mediated delivery of macromolecular anticancer therapeutic agents

    Adv. Drug Deliv. Rev.

    (2012)
  • F. Agustoni et al.

    EGFR-directed monoclonal antibodies in combination with chemotherapy for treatment of non-small-cell lung cancer: an updated review of clinical trials and new perspectives in biomarkers analysis

    Canc. Treat Rev.

    (2019)
  • R. Gupta et al.

    Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma: the need to test neoplasms with more than one method

    Mod. Pathol.

    (2009)
  • M. Ladanyi et al.

    Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond

    Mod. Pathol.

    (2008)
  • N. Parker et al.

    Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay

    Anal. Biochem.

    (2005)
  • M.I. Nunez et al.

    High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and mutation

    J. Thorac. Oncol.

    (2012)
  • D.C. Christoph et al.

    Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed

    J. Thorac. Oncol.

    (2013)
  • K. Holmes et al.

    Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition

    Cell. Signal.

    (2007)
  • M.A. Lemmon et al.

    Cell signaling by receptor tyrosine kinases

    Cell

    (2010)
  • R. Roskoski

    Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition

    Pharmacol. Res.

    (2013)
  • L.A. Torre et al.

    Global cancer statistics

    Ca - Cancer J. Clin.

    (2012)
  • S.S. Ramalingam et al.

    Lung cancer: new biological insights and recent therapeutic advances

    CA: Canc. J. Clin.

    (2011)
  • L. Sercombe et al.

    Advances and challenges of liposome assisted drug delivery

    Front. Pharmacol.

    (2015)
  • M.H. Pourhanifeh et al.

    Melatonin and non-small cell lung cancer: new insights into signaling pathways

    Canc. Cell Int.

    (2019)
  • Cancer statistics - specific cancers

    (2019)
  • R. Nall

    Lung cancer: symptoms, treatment, and early diagnosis, Med

    (2018)
  • T. Yano et al.

    Therapeutic strategy for postoperative recurrence in patients with non-small cell lung cancer

    World J. Clin. Oncol.

    (2014)
  • D.S. Shewach et al.

    Introduction to cancer chemotherapeutics

    Chem. Rev.

    (2009)
  • D. Peer et al.

    Nanocarriers as an emerging platform for cancer therapy

    Nat. Nanotechnol.

    (2007)
  • Y. Luo et al.

    Cancer-targeted polymeric drugs

    Curr. Cancer Drug Targets

    (2005)
  • I. Vhora et al.

    Receptor-targeted drug delivery: current perspective and challenges

    Ther. Deliv.

    (2014)
  • H. Nehoff et al.

    Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect

    Int. J. Nanomed.

    (2014)
  • O.C. Farokhzad et al.

    Impact of nanotechnology on drug delivery

    ACS Nano

    (2009)
  • P. Kumari et al.

    Nanocarriers for cancer-targeted drug delivery

    J. Drug Target.

    (2016)
  • E. Luque-Michel et al.

    Clinical advances of nanocarrier-based cancer therapy and diagnostics

    Expet Opin. Drug Deliv.

    (2017)
  • S. Hirsjarvi et al.

    Passive and active tumour targeting with nanocarriers

    Curr. Drug Discov. Technol.

    (2011)
  • W. Yu et al.

    Surface modification of nanocarriers for cancer therapy

    Curr. Nanosci.

    (2009)
  • A.Z. Wang et al.

    Nanoparticle delivery of cancer drugs

    Annu. Rev. Med.

    (2012)
  • Cited by (19)

    • Advances and challenges in the treatment of lung cancer

      2023, Biomedicine and Pharmacotherapy
    • Afatinib liposomal dry powder inhaler: Targeted pulmonary delivery of EGFR inhibitor for the management of lung cancer

      2022, Journal of Drug Delivery Science and Technology
      Citation Excerpt :

      Genetic as well as environmental factors along with a contact to arsenic, asbestos, toxins, radon gas are the other risk factors that enhance the chances of lung cancer. The cases of lung cancer in non-smokers account for approximately 10–15% [4]. Generally, intravenously, or orally administered chemotherapeutic drugs reach the cancerous cells throughout the body once it is transient through the bloodstream.

    • Effective strategies of sustained release and retention enhancement of essential oils in active food packaging films/coatings

      2022, Food Chemistry
      Citation Excerpt :

      In summary, the addition of microencapsulated EO into active films/coatings could enhance EO's application efficiency for the food packaging applications and improve other properties of active films/coatings, such as mechanical properties and barrier properties. Nanomaterials refer to natural or manufactured materials that contain particles in the form of dissociation or aggregate/agglomerate with a size of 1–100 nm (Vanza, Patel, & Patel, 2020). Encapsulated nanoparticles containing EO commonly prepared by different biopolymers through ion aggregation or nanoprecipitation technology (Doost et al., 2020).

    View all citing articles on Scopus
    View full text