Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance

Abstract

Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.inhalation | antisense oligonucleotides | liposomes | orthotopic lung cancer model | pump and nonpump resistance L ung cancer is the leading cause of cancer-related death worldwide (1). Because of the size and distribution of lung cancer, cytoreductive surgery is not very effective for this disease, and therefore chemotherapy and/or radiation are the treatments of choice. However, despite the advances in cancer treatment and improvements in lifestyle and health care, death rates from lung cancer have not changed significantly over the last 50 years. In contrast, mortality from heart disease, the leading cause of death, declined almost 2.5-fold over the same period (2). The patient survival has been in a plateau for three decades (3), with a 5-year relative survival rate of less than 18% in most countries (4). The efficacy of chemotherapy in lung cancer is limited by the rapid development of cancer cell resistance during treatment. To overcome this resistance, higher doses of toxic anticancer drug(s) are administered, often producing adverse side effects in healthy organs. We hypothesize that a substantial enhancement in the efficiency of lung cancer treatment is possible by (i) local delivery of chemotherapeutic agent(s) by inhalation and (ii) simultaneous suppression of at least major mechanisms of lung cancer cell resistance. Local delivery of anticancer drugs directly into the lungs will increase their accumulation in tumor cells and will reduce adverse side effects on healthy organs by limiting drug concentration in the blood. Simultaneous suppression of cellular resistance in tumors will increase the intracellular concentration of the drug in cancer cells and enhance its cytolethality for cancerous cells.Patients with asthma and chronic obstructive pulmonary disease commonly use inhaled drugs (5). Although some chemotherapeutic agents can be delivered through the pulmonary or intratracheal route (6-9), most anticancer drugs cannot be inhaled in t...

Characterization and Application of a Nose-Only Exposure Chamber for Inhalation Delivery of Liposomal Drugs and Nucleic Acids to Mice

“…Recently, we demonstrated that the efficacy of the chemotherapy can be substantially enhanced if both resistance mechanisms are simultaneously suppressed when an anticancer agent(s) is delivered. (3)(4)(5) We also showed that antisense oligonucleotides (ASO) and small interfering RNA (siRNA) can be efficiently used to suppress both types of resistance. (6)(7)(8) However, ASO and siRNA poorly penetrate cancer cells, are unstable in the bloodstream, and therefore require a special carrier system to preserve their activity in the extracellular environment and increase their accumulation in cancer cells.…”

“…(11) When it comes to anticancer drugs, inhalation delivery would enhance the accumulation of anticancer agent(s) in the lungs with tumor and reduce severe toxic side effects on healthy tissues. (5) Inhaled drugs are commonly used by patients with asthma and chronic obstructive pulmonary disease. (12) Although some chemotherapeutic agents can be delivered through the pulmonary or intratracheal route, (13)(14)(15)(16) most anticancer drugs, as well as resistance suppressors ASO and siRNA, cannot be inhaled in their traditional form and require a special drug carrier system (DCS).…”

“…(26,27) When the liposomes are administered systemically, their residence time in the circulatory system is short due to elimination by the reticuloendothelial system, which limits their therapeutic application. (28,29) In contrast, delivery of liposomal drugs via inhalation increases drug retention time in the lungs (5,25) and reduces extrapulmonary side effects. (5,30) Consequently, delivery of anticancer agent(s) together with suppressor(s) of cancer cell resistance in one DCS directly to the lung via inhalation would be capable of substantially enhancing the efficacy of the treatment of lung cancer and limiting the adverse side effects of chemotherapy on healthy organs.…”

“…(28,29) In contrast, delivery of liposomal drugs via inhalation increases drug retention time in the lungs (5,25) and reduces extrapulmonary side effects. (5,30) Consequently, delivery of anticancer agent(s) together with suppressor(s) of cancer cell resistance in one DCS directly to the lung via inhalation would be capable of substantially enhancing the efficacy of the treatment of lung cancer and limiting the adverse side effects of chemotherapy on healthy organs. This approach is the focus of our ongoing study, and substantial progress and encouraging results have already been reported in an animal (mouse) model.…”

“…This approach is the focus of our ongoing study, and substantial progress and encouraging results have already been reported in an animal (mouse) model. (5,25) Once a suitable DCS, such as liposomes, is developed and prepared to carry out in vivo testing, it has to be aerosolized and delivered to test animals for inhalation exposure in a way that does not affect the efficacy of its active ingredients. As an aerosolization method could potentially affect the integrity of the DCS, as well as its airborne number and mass distributions, these variables have to be explored before the actual animal exposures can begin.…”