In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug

Pakunlu, Refika I.; Wang, Yan; Saad, Maha; Khandare, Jayant; Starovoytov, Valentin; Minko, Tamara

doi:10.1016/j.jconrel.2006.06.010

Cited by 117 publications

(98 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cy5.5 represents a class of very effective dyes currently used as cancer imaging agents. The systems were prepared and characterized using procedures previously developed in our laboratory [7,[23][24][25][26][27][28]. Based on the results of dynamic light scattering and atomic force microscope measurements, the average size of dendrimers, PEG polymers, and liposomes were about 5, 30 and 100 nm respectively.…”

Section: Nanocarriersmentioning

confidence: 99%

Receptor targeted polymers, dendrimers, liposomes: Which nanocarrier is the most efficient for tumor-specific treatment and imaging?

Saad

Garbuzenko

Ber

et al. 2008

Journal of Controlled Release

Self Cite

219

165

View full text Add to dashboard Cite

To compare the influence of different characteristics of nanocarriers on the efficacy of chemotherapy and imaging, we designed, characterized, and evaluated three widely used nanocarriers: linear polymer, dendrimer and liposome in vitro and in vivo. These nanocarriers delivered the same anticancer drug (paclitaxel) and/or imaging agent (Cy5.5). A synthetic analog of LHRH peptide targeted to receptors overexpressed on the membrane of cancer cells was attached to the nanocarriers as a tumor targeting moiety. Significant differences were found between various studied non-targeted carriers in their cellular internalization, cytotoxicity, tumor and organ distribution and anticancer efficacy. LHRH peptide substantially enhanced intratumoral accumulation and anticancer efficacy of all delivery systems and minimized their adverse side effects. For the first time, the present study revealed that the targeting of nanocarriers to tumorspecific receptors minimizes the influence of the architecture, composition, size and molecular mass of nanocarriers on the efficacy of imaging and cancer treatment.

show abstract

Section: Nanocarriersmentioning

confidence: 99%

Receptor targeted polymers, dendrimers, liposomes: Which nanocarrier is the most efficient for tumor-specific treatment and imaging?

Saad

Garbuzenko

Ber

et al. 2008

Journal of Controlled Release

Self Cite

219

165

View full text Add to dashboard Cite

show abstract

“…Targeted drug delivery systems (DDSs) designed to achieve this goal consist of affinity vectors (e.g., antibodies directed to endothelial surface determinants) coupled either directly to pharmacological cargoes (e.g., therapeutic enzymes) or to drugloaded vehicles or carriers (e.g., liposomes or polymer nanocarriers) [8][9][10][11][12][13][14]. Endothelial targeting of DDSs carrying reporter probes, enzymes, other drugs, genes and/or drug nanocarriers has been achieved in a number of animal species and even in a few "proof of principal" human studies (reviewed in [1,8]).…”

Section: Introductionmentioning

confidence: 99%

Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium

Shuvaev

Christofidou‐Solomidou

Scherpereel

et al. 2007

Journal of Controlled Release

View full text Add to dashboard Cite

Vascular drug targeting may improve therapies, yet a thorough understanding of the factors that regulate effects of drugs directed to the endothelium is needed to translate this approach into the clinical domain. To define factors modulating the efficacy and effects of endothelial targeting, we used a model enzyme (glucose oxidase, GOX) coupled with monoclonal antibodies (anti-TM 34 or anti-TM 201 ) to distinct epitopes of thrombomodulin, a surface determinant enriched in the pulmonary endothelium. GOX delivery results in conversion of glucose and oxygen into H 2 O 2 leading to lung damage, a clear physiologic endpoint. Results of in vivo studies in mice showed that the efficiency of cargo delivery and its effect are influenced by a number of factors including: 1) The level of pulmonary uptake of the targeting antibody (anti-TM 201 was more efficient than anti-TM 34 ); 2) The amount of an active drug delivered to the target; 3) The amount of target antigen on the endothelium (animals with suppressed TM levels showed less targeting); and, 4) The substrate availability for the enzyme cargo in the target tissue (hyperoxia augmented GOX-induced injury). Therefore, both activity of the conjugates and biological factors control targeting and effects of enzymatic cargo. Understanding the nature of such "modulating biological factors" will hopefully allow optimization and ultimately applications of drug targeting for "individualized" pharmacotherapy.

show abstract

“…Nonpump drug resistance is primarily attributed to the activation of antiapoptotic cellular defense, and BCL2 protein is a key player in this defense. Similarly to MRP1, the expression of BCL2 protein increases substantially after the treatment with anticancer drugs (19,20,23,(27)(28)(29).Consequently, it is logical to hypothesize that local pulmonary delivery of anticancer agents, combined with simultaneous suppression of pump and nonpump resistance, would be capable of substantially enhancing the efficacy of treatment of lung cancer and limiting adverse side effects of chemotherapy on healthy organs. To test this hypothesis, we designed and examined, in an orthotopic murine model of human lung cancer, a complex system that allows inhalation local delivery of an anticancer drug (DOX) combined with suppressors of pump and nonpump resistance (ASO targeted to MRP1 and BCL2 mRNA, respectively).…”

mentioning

confidence: 99%

“…Two main mechanisms are responsible for the resistance of cancer cells against chemotherapy: pump and nonpump resistance (18)(19)(20)(21)(22)(23). Pump resistance is caused by membrane efflux pumps that decrease the anticancer drug concentration inside the cells.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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.

Self Cite

167

149

View full text Add to dashboard Cite

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...

show abstract

In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug

Cited by 117 publications

References 38 publications

Receptor targeted polymers, dendrimers, liposomes: Which nanocarrier is the most efficient for tumor-specific treatment and imaging?

Receptor targeted polymers, dendrimers, liposomes: Which nanocarrier is the most efficient for tumor-specific treatment and imaging?

Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium

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

Contact Info

Product

Resources

About