Fast degrading polyesters as siRNA nano-carriers for pulmonary gene therapy

Nguyen, Juliane; Steele, Terry W. J.; Merkel, Olivia M.; Reul, Regina; Kissel, Thomas

doi:10.1016/j.jconrel.2008.06.010

Cited by 129 publications

(90 citation statements)

References 46 publications

(55 reference statements)

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“…The use of polymeric nanoparticle systems for drug and vaccine delivery offers several advantages, including controlled delivery of encapsulated payload(s) and, depending on their chemical properties, improved biocompatibility, receptor targeting capabilities, sustained antigen/drug release kinetics, adjuvanticity, and opportunities for both local and systemic delivery (12,13). Polyanhydride nanoparticles have displayed these characteristics in both in vitro and/or in vivo settings (6,9,(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

Vela-Ramirez

Goodman

Boggiatto

et al. 2014

AAPS J

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ABSTRACT. Carbohydrate functionalization of nanoparticles allows for targeting of C-type lectin receptors. This family of pattern recognition receptors expressed on innate immune cells, such as macrophages and dendritic cells, can be used to modulate immune responses. In this work, the in vivo safety profile of carbohydrate-functionalized polyanhydride nanoparticles was analyzed following parenteral and intranasal administration in mice. Polyanhydride nanoparticles based on 1,6-bis-(pcarboxyphenoxy)hexane and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane were used. Nanoparticle functionalization with di-mannose (specifically carboxymethyl-α-D-mannopyranosyl-(1,2)-Dmannopyranoside), galactose (specifically carboxymethyl-β-galactoside), or glycolic acid induced no adverse effects after administration based on histopathological evaluation of liver, kidneys, and lungs. Regardless of the polymer formulation, there was no evidence of hepatic or renal damage or dysfunction observed in serum or urine samples. The histological profile of cellular infiltration and the cellular distribution and kinetics in the lungs of mice administered with nanoparticle treatments followed similar behavior as that observed in the lungs of animals administered with saline. Cytokine and chemokine profiles in bronchoalveolar lavage fluid indicated surface chemistry dependence on modest secretion of IL-6, IP-10, and MCP-1; however, there was no evidence of any deleterious histopathological changes. Based on these analyses, carbohydrate-functionalized nanoparticles are safe for in vivo applications. These results provide foundational information towards the evaluation of the capabilities of these surface-modified nanoparticles as vaccine delivery formulations.

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Section: Introductionmentioning

confidence: 99%

Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

Vela-Ramirez

Goodman

Boggiatto

et al. 2014

AAPS J

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“…Recently, several different DDS have been developed for inhalation delivery of different drugs. Liposomes (10-13), lipid-and polymerbased nanoparticles (14)(15)(16)(17), are the most frequently used carriers for local pulmonary delivery of different drugs, antisense oligonucleotides (ASO), and short-interfering RNA (siRNA).…”

mentioning

confidence: 99%

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.

167

149

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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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“…Previous work carried out by us demonstrated that microparticles of 2.1 µm in size were optimal for cell uptake in primary alveolar macrophages and differentiated THP-1 cells, and can be further enhanced through coating with gelatin [120]. For efficient pulmonary delivery the optimum mass median aerodynamic diameter (MMAD) of particles ranges between 1 µm to 5 µm that can be achieved using a range of manufacturing processes for PLGA microparticles [121]. Whilst size can be optimized through variations in manufacturing, encapsulation efficiency for siRNA in PLGA microparticles is poor.…”

Section: Microparticles For Targeting Amsmentioning

confidence: 99%

‘Smart‘ non-viral Delivery Systems for Targeted Delivery of RNAi to the Lungs

Ramsey

Hibbitts

Barlow

et al. 2012

Therapeutic Delivery

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SummaryThe emergence of RNA interference (RNAi) offers a potentially exciting new therapeutic paradigm for respiratory diseases. However effective delivery remains a key requirement for their translation into the clinic and has been a major factor in the limited clinical success seen to-date. Inhalation offers tissue-specific targeting of the RNAi to treat respiratory diseases and a diminished risk of off-target effects. In order to deliver RNAi directly to the respiratory tract via inhalation "smart" non-viral carriers are required to protect the RNAi during delivery/aerosolisation and enhance cell-specific uptake to target cells. Herein, we review the state of the art in therapeutic aerosol bioengineering (TAB) and specifically non-viral siRNA delivery platforms for delivery via inhalation. This includes developments in inhaler device engineering and particle engineering including manufacturing methods and excipients used in TAB that underpin the development of "smart" cell-type specific delivery systems to target siRNA to respiratory epithelial cells and/or alveolar macrophages.

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Fast degrading polyesters as siRNA nano-carriers for pulmonary gene therapy

Cited by 129 publications

References 46 publications

Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

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

‘Smart‘ non-viral Delivery Systems for Targeted Delivery of RNAi to the Lungs

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