Intratracheal Versus Intravenous Liposomal Delivery of siRNA, Antisense Oligonucleotides and Anticancer Drug

Garbuzenko, Olga B.; Saad, Maha; Betigeri, Seema; Zhang, Min; Vetcher, Alexandre A.; Soldatenkov, Viatcheslav A.; Reimer, David; Pozharov, Vitaly P.; Minko, Tamara

doi:10.1007/s11095-008-9755-4

Cited by 148 publications

(101 citation statements)

References 42 publications

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“…5B). Similar profiles of organ distribution were found also for DOX and liposomes (12). The calculation of content of ASO per gram tissue in different organs also showed their preferential accumulation in the lungs after inhalation administration (Fig.…”

Section: Resultssupporting

confidence: 80%

“…First, we had to incorporate neutral P-ethoxy modified antisense oligonucleotides and doxorubicin in one liposome; consequently, we had to use neutral liposomes because loading efficiency of neutral ASO and DOX into charged liposomes is low. Second, our previous data (12) showed that PEGylated neutral liposomes provided for the most favorable accumulation and retention of liposomes and their payload in the lungs after inhalation delivery.…”

Section: Methodsmentioning

confidence: 98%

“…P-ethoxy modified antisense oligonucleotides targeted to MRP1 (5′-TGC TGT TCG TGC CCC CGC CG-3′) and BCL2 (5′-CAG CGT GCG CCA TCC TTC CC-3′) mRNA were synthesized according to our design by Oligos Etc. PEGylated liposomes containing DOX and ASO were prepared as previously described (12). The selection of neutral PEGylated liposomes was based on the following considerations.…”

Section: Methodsmentioning

confidence: 99%

“…Comparison of the local pulmonary and systemic i.v. administration of drugs, ASO, and siRNA showed that pulmonary delivery provides for a better retention of active ingredients in the lungs and minimizes their penetration into the systemic circulation (6,7,12,17), prerequisites for limiting adverse side effects of chemotherapy.Two main mechanisms are responsible for the resistance of cancer cells against chemotherapy: pump and nonpump resistance (18-23). Pump resistance is caused by membrane efflux pumps that decrease the anticancer drug concentration inside the cells.…”

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

Garbuzenko¹,

Saad²,

Pozharov³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Resultssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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