Choice of nanocarrier for pulmonary delivery of cancer therapeutics

Abstract

Lung cancer can be classified as primary and secondary cancers [1]. The primary lung cancer has the carcinoma cells originated from the lung tissues. The secondary lung cancer is characterized by carcinoma cells contracted through blood or lymphatic system. The lung cancer is histologically divided into small cell lung carcinoma and non-small cell lung carcinoma representing about 96% of lung cancer, mesothelioma, carcinoid, and sarcoma. Small cell lung carcinoma locates in the central area of the lungs mainly in the bronchi. The non-small cell lung carcinoma tends to locate in the peripheral lungs. Globally, lung cancer is the main and second cause of cancer-related death among men and women, respectively, with very low survival rates. Patients with lung cancer are treated with several therapeutic procedures such as surgery, radiotherapy, chemotherapy, and molecular-targeted therapies. Chemotherapy is usually administered to the patients as neo-adjuvant or adjuvant therapy. It is an essential treatment mode especially in advanced lung cancer where metastasis prevails. Gene therapy has been the recent focus of research [2,3]. Small interfering ribonucleic acid (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA) are examples of RNAi-based therapeutics that can either be delivered through systemic administration or local administration to negate the expression of intended gene and cancer. The delivery of RNAi-based therapeutics through systemic administration may bring about adverse effects such as liver toxicity, therapeutic instability, and stimulation of immune response. Pulmonary administration of RNAibased therapeutics is deemed to be a better delivery approach in targeting the cancer tissue [4]. The United States Food and Drug Administration (US FDA) stated two ‘points to consider’ in defining an FDA-regulated nanoproduct. First, the material or end product is engineered to have at least one external dimension or an internal or surface structure, in the nanoscale ranges approximately 1 nm to 100 nm. Alternatively, the material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to 1000 nm [1,5]. Nanocarriers are entities that are constructed from nanomaterials which add additional functionality to the therapeutics. Examples of nanocarriers are nanocrystals, nanosuspension, lipid-based nanocarriers, polymeric-based nanocarriers, and inorganic nanocarriers. The nanocarrier is adopted to protect drugs from degradation, sustain its delivery, improve its dissolution, effect drug targeting, overcoming absorption barrier and increasing drug bioavailability to enable the reduction of drug dose and related adverse effects. The conjugation of nanocarrier with a targeting ligand to drive the therapeutics to cancer cells or organelles instead of the normal population promotes the specificity of drug action and minimizes the drug toxicity. With reference to inhalation, dry powder inhalers and nebulizers are devices commonly being exploited for pulmonary delivery of therapeutical nanocarrier to deeper lung regions. Nebulizers generate liquid aerosols by breaking down the liquid dosage form into fine tiny droplets for inhalation by either compressed air or ultrasonic power. Dry powder inhaler mediates inhalation with the airflow created by the user directing through a drug powder thus generating inhalable dry powder aerosol. The late evaluation of inhalation profiles of liquid and solid nanotherapeutics from nebulizer and dry powder inhaler, respectively, shows that the percentages of therapeutic inhaled are generally lower with dry powder inhalation than liquid nebulization by more than two folds [6,7]. Dry powder inhalation has been advocated as the choice of pulmonary drug delivery as a solid product is characterized by a high physicochemical quality [8]. Nonetheless, the delivery of nanocarrier via dry powder inhalation is limited by their submicron size. A large fraction of nanocarrier will be exhaled after inhalation thus failing deep and peripheral lung drug deposition for cancer treatment. The nanocarrier is aggregative due to its large specific surface area and inter-particle forces. The formed aggregates are less able to redisperse to release nanocarrier again, and the powder becomes very difficult to handle [9]. To enable dry nanopowder inhalation, the nanocarrier has been transformed into nanoagglomerates, nanocomposites, nanocarrier loaded microparticles and lyophilized floccules with mass median aerodynamic diameter between 1 and 5 μm [1]. Nonetheless, poor nanocarrier