Polymeric Nanoparticle-Mediated Gene Delivery for Lung Cancer Treatment
Narsireddy Amreddy 0 1 2 3
Anish Babu 0 1 2 3
Ranganayaki Muralidharan 0 1 2 3
Anupama Munshi 0 1 2 3
Rajagopal Ramesh 0 1 2 3
0 Stephenson Cancer Center, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA
1 Department of Radiation Oncology, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA
2 Department of Pathology, Stanton L. Young Biomedical Research Center, University of Oklahoma Health Sciences Center , Suite 1403, 975 N.E., 10th Street, Oklahoma City, OK 73104 , USA
3 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center , Oklahoma City, OK , USA
In recent years, researchers have focused on targeted gene therapy for lung cancer, using nanoparticle carriers to overcome the limitations of conventional treatment methods. The main goal of targeted gene therapy is to develop more efficient therapeutic strategies by improving the bioavailability, stability, and target specificity of gene therapeutics and to reduce off-target effects. Polymer-based nanoparticles, an alternative to lipid and inorganic nanoparticles, efficiently carry nucleic acid therapeutics and are stable in vivo. Receptor-targeted delivery is a promising approach that can limit non-specific gene delivery and can be achieved by modifying the polymer nanoparticle surface with specific receptor ligands or antibodies. This review highlights the recent developments in gene delivery using synthetic and natural polymer-based nucleic acid carriers for lung cancer treatment. Various nanoparticle systems based on polymers and polymer combinations are discussed. Further, examples of targeting ligands or moieties used in targeted, polymer-based gene delivery to lung cancer are reviewed.
1 Introduction
Lung cancer is the leading cause of cancer-related mortality in both men and women
[1]. Two main subtypes of lung cancer exist: (1) non-small cell lung cancer
(NSCLC) and (2) small cell lung cancer (SCLC). NSCLC accounts for about 85% of
lung cancers, with the remaining 15% characterized as SCLC. NSCLC has three
subtypes: (1) adenocarcinoma, (2) squamous cell carcinoma, and (3) large-cell
carcinoma. Approximately 40% of lung cancers are adenocarcinomas, which
originate in the peripheral lung tissue. Twenty-five percent of lung cancers are
squamous cell carcinomas, which originate from proximal airway epithelial cells;
large cell carcinoma originating from epithelial cells accounts for 15% of lung
cancer cases [2].
The conventional treatment methods for lung cancer are surgery, radiotherapy,
and chemotherapeutics [3, 4]. These treatment methods have some limitations
because of their poor therapeutic efficiency, non-specific interactions, and toxicity
to normal tissues [5]. Gene therapy is an alternative approach that can improve
therapeutic efficiency and reduce toxicity to normal tissues [6, 7].
In cancer therapy, RNAi has been recognized as an efficient method of targeted
therapy that is facilitated through target-specific oligonucleotides that knock down
expression of the genes [8]. RNAi can be achieved using small interfering RNA
(siRNA), short hairpin RNA (shRNA), and micro RNA (miRNA), which has an
average of 21–23 base pair oligonucleotides [9]. The targeted delivery of genes into
cancer cells results in the specific silencing of genes that are actively involved in
tumor growth, angiogenesis, and metastasis [10, 11]. For successful and efficient
gene delivery, oligonucleotides need carrier support to transfect into cells because
of the possibility of degradation by nucleases while circulating and in the harsh
conditions of cellular endo-lysosomes [12]. Nanoparticles are promising carriers for
transfecting genes into cancer cells. Among the different types of nanoparticles,
polymer-based nanoparticles are widely used for gene delivery [13].
Most polymer-based nanoparticles exhibit a positive surface charge on the
periphery, which is utilized for electrostatic adsorption and condensation of nucleic
acids [14, 15]. Synthetic and natural polymers of different architecture can form
nano- or micro-sized particles, depending on the chemical methods used for
synthesis [16]. Biocompatibility and biodegradability are important parameters that
must be considered when polymers are chosen for gene delivery vehicle fabrication.
Moreover, many polymers used in gene delivery systems actively exhibit a ‘‘proton
sponge effect’’ that initiates the endo-lysosomal escape of therapeutic gene
molecules into the cytoplasm [17]. Further, the polymer’s surface functionality also
plays an important role in conjugating biomolecules for therapeutic targeting into
cancer cells [18]. The specific delivery into cancer cells is an important strategy to
improve therapeutic efficacy and reduce toxicity in normal tissues.
Ligand-based targeting is more promising than other passive and physical
targeting methods for gene delivery. Ligands attached to the surface of
nanoparticles specifically interact wi (...truncated)