Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

Park, Kitae; Hong, Sung Woo; Hur, Wonhee; Lee, Min Young; Yang, Jeong-A; Kim, Sung Woo; Yoon, Seung Kew; Hahn, Sei Kwang

doi:10.1016/j.biomaterials.2011.03.044

Cited by 58 publications

(24 citation statements)

References 25 publications

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“…A number of studies have provided proof of concept that at least stellate cells can be specifically targeted; by taking advantage of the expression of the mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II) receptor on stellate cells, it has been elegantly demonstrated that M6P-modified albumins conjugated to specific inhibitors or toxins reduced stellate cell mediated fibrogenesis 144, 175 . Alternatively, it is possible that physical properties of activated stellate cells may be taken advantage of, and that stellate cells could be targeted with specialized liposomes or similar compounds 176–178 .…”

Section: Challenges In Developing Anti-fibrotic Therapymentioning

confidence: 99%

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Rockey

2013

Clinical Gastroenterology and Hepatology

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The response to injury is one of wound healing and fibrogenesis, which ultimately leads to fibrosis. The fibrogenic response to injury is a generalized one across virtually all organ systems. In the liver, the injury response, typically occuring over a prolonged period of time, leads to cirrhosis (although it should be pointed out that not all patients with liver injury develop cirrhosis). The fact that many different diseases result in cirrhosis suggests a common pathogenesis. The study of hepatic fibrogenesis over the past 2 decades has been remarkably active, leading to a considerable understanding of this process. It has been clearly demonstrated that the hepatic stellate cell is a central component in the fibrogenic process. It has also been recognized that other “effector” cells are important in the fibrogenic process, including resident fibroblasts, bone marrow derived cells, fibrocytes, and even perhaps cells derived from epithelial cells (i.e., through epithelial to mesenchymal transition or EMT). A key aspect of the biology of fibrogenesis is that the fibrogenic process is dynamic; thus, even advanced fibrosis (or cirrhosis) is reversible. Together, an understanding of the cellular basis for liver fibrogenesis, along with multiple aspects of the basic pathogenesis of fibrosis, have highlighted many exciting potential therapeutic opportunities. Thus, while the most effective “anti-fibrotic” therapy is treatment of the underlying disease, in situations in which this not possible, specific anti-fibrotic therapy is likely to not only become feasible, but will soon become a reality. The goal of this review is to highlight the mechanisms underlying fibrogenesis that may be translated into future anti-fibrotic therapies and to review the current state of clinical development.

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Section: Challenges In Developing Anti-fibrotic Therapymentioning

confidence: 99%

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Rockey

2013

Clinical Gastroenterology and Hepatology

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“…Taken together, these results suggest potential advantages of negatively charged gene and drug delivery reagents for passive tumor targeting and warrant further investigation using polycations or other polymeric delivery reagents. The system recently developed by Park et al may conform to this and perform admirably, as it releases the amphiphilic structure and still remains complexed [32]. Unfortunately, this was an intratumoral injection, so a direct comparison cannot be made.…”

Section: Discussionmentioning

confidence: 99%

Functional properties and biodistribution of poly(triethylenetetramine/cystamine bisacrylamide) and poly(triethylenetetramine/cystamine bisacrylamide)- poly(ethylene glycol) mixtures formed with nucleic acid

Brumbach

Lee

Kim

et al. 2012

Journal of Controlled Release

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The clinical success of non-viral gene delivery reagents is hampered by their inefficient cellular transgene delivery, which is largely influenced by carrier properties that are currently undefined and misunderstood. In an attempt to further define and understand the requirements for a safe and efficient non-viral gene delivery reagent, research labs often engineer and evaluate many putative products with subtle physiochemical differences in order to delineate requirements for improved in vitro and in vivo success. The synthesis of many putative reagents is often time-intensive, laborious and costly. In a previous manuscript published by our lab, different amounts of poly(triethylenetetramine/cystamine bisacrylamide) (p(TETA/CBA) and its pegylated counterpart, poly(triethylenetetramine/cystamine bisacrylamide)- poly(ethylene glycol) (p(TETA/CBA)-g-PEG) were mixed together to easily identify optimal reagent properties and candidates in vitro, while avoiding the synthesis of many putative candidates for study. This report uses the aforementioned facile approach to evaluate reagent properties of products that were obtained via one-pot synthesis, which improved synthetic ease. As such, synthesis time was reduced from 6 days to 3 days and had comparable or improved transfection and viability compared to previous works. Moreover, this synthesis resulted in higher molecular weight products than were used in the previous study and allow for lower polymer doses to be used for complexation, which is useful for systemic delivery that is used herein. The physiochemical properties of the formulations derived using these novel reagents was studied prior to investigating their in vivo biodistribution profiles in a murine colon adenocarcinoma model. Interestingly, negatively charged complexes exhibited greater passive tumor accumulation compared to positively charged complexes following their systemic administration. These studies warrant further investigation for the use of negatively charged drug and gene delivery reagents for passive tumor targeting, and they substantiate the use of polycation/PEG-polycation mixtures for facile product evaluation in order to elucidate design and formulation mandates for the clinical success of non-viral gene delivery formulations.

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“…In addition, HA is used along with cationic liposomes and polymers to reduce cytotoxicity and their interaction with serum proteins [95]. For example, HA conjugated with polyethyleneimine (HA–PEI) was used for the delivery of siRNA and has shown effective gene silencing effect in vitro [96] and in vivo [97,98]. The presence of HA prevented particle aggregation in blood and death related to pulmonary embolism [97].…”

Section: Hyaluronic Acidmentioning

confidence: 99%

“…For example, HA conjugated with polyethyleneimine (HA–PEI) was used for the delivery of siRNA and has shown effective gene silencing effect in vitro [96] and in vivo [97,98]. The presence of HA prevented particle aggregation in blood and death related to pulmonary embolism [97]. The mechanism by which the siRNA/HA–PEI complex enters cells remains controversial [96,98], but there is a possibility of receptor-mediated endocytosis, given that the siRNA–HA–PEI complex, unlike siRNA–PEI, tends to accumulate in the tissues with HA receptors [27,98].…”

Section: Hyaluronic Acidmentioning

confidence: 99%

Application of Polysaccharides for Surface Modification of Nanomedicines

Doh

Yeo

2012

Therapeutic Delivery

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Polysaccharides have been used in various biomedical applications due to availability and biocompatibility. In particular, polysaccharides have gained increasing interest in the development of functional nanomedicines as a component to provide a stealth function, improve interactions with target tissues or enable environment-responsive drug release. This review discusses recent advances in nanomedicine engineering based on polysaccharides with a specific emphasis on the rationale, applications and the remaining challenges.

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Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

Cited by 58 publications

References 25 publications

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Functional properties and biodistribution of poly(triethylenetetramine/cystamine bisacrylamide) and poly(triethylenetetramine/cystamine bisacrylamide)- poly(ethylene glycol) mixtures formed with nucleic acid

Application of Polysaccharides for Surface Modification of Nanomedicines

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