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Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid
Charles M Rudin1, John L Marshall, Chao Hui Huang
1The University of Chicago, Chicago, Illinois, USA. rudin@jhmi.edu
Purpose:
Rapid cleavage in vivo and inefficient cellular uptake limit the clinical utility of antisense oligonucleotides (AON). Liposomal formulation may promote better intratumoral AON delivery and inhibit degradation in vivo. We conducted the first clinical evaluation of this concept using a liposomal AON complementary to the c-raf-1 proto-oncogene (LErafAON).
Experimental Design:
A dose escalation study was done to determine the maximum tolerated dose and to characterize the toxicities of LErafAON given as weekly intravenous infusion for 8 weeks to adults with advanced solid tumors. Pharmacokinetic analysis and evaluation of c-raf-1 target suppression in peripheral blood mononuclear cells were included.
Results:
Twenty-two patients received LErafAON (median 7 infusions; range 1-27) at doses of 1, 2, 4, and 6 mg/kg/week. Across all dose cohorts patients experienced infusion-related hypersensitivity reactions including flushing, dyspnea, hypoxia, rigors, back pain, and hypotension. Prolonged infusion duration and pretreatment with acetaminophen, H1- and H2-antagonists, and corticosteroids reduced the frequency and severity of these reactions. Progressive thrombocytopenia was dose-limiting at 6 mg/kg/week. No objective responses were observed. Two patients treated at the maximum tolerated dose of 4 mg/kg/week had evidence of stable disease, with dosing extended beyond 8 weeks. Pharmacokinetic analysis revealed persistence of detectable circulating rafAON at 24 hours in 7 of 10 patients in the highest 2 dose cohorts. Suppression of c-raf-1 mRNA was noted in two of five patients analyzed.
Conclusions:
Dose-independent hypersensitivity reactions and dose-dependent thrombocytopenia limited tolerance of LErafAON. Future clinical evaluation of this approach will depend on modification of the liposome composition.
Insights
Liposomal antisense oligonucleotides (AON) showed limited tolerance due to hypersensitivity and thrombocytopenia. Further modifications are needed for clinical use of this c-raf-1 targeted therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Antisense oligonucleotides (AON) face challenges with rapid in vivo degradation and poor cellular uptake, limiting their therapeutic potential.
- Liposomal formulations offer a strategy to enhance intratumoral delivery and protect AON from degradation.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, and target engagement of a liposomal AON targeting the c-raf-1 proto-oncogene (LErafAON) in patients with advanced solid tumors.
- To determine the maximum tolerated dose (MTD) of LErafAON.
Main Methods:
- A phase I dose-escalation study administered LErafAON intravenously weekly for 8 weeks.
- Pharmacokinetic analysis and assessment of c-raf-1 mRNA suppression in peripheral blood mononuclear cells were performed.
- Management of infusion-related reactions included prolonged infusion and premedication.
Main Results:
- Twenty-two patients received LErafAON at doses up to 6 mg/kg/week. Infusion-related hypersensitivity reactions were common but manageable.
- Dose-limiting toxicity was progressive thrombocytopenia at 6 mg/kg/week, establishing the MTD at 4 mg/kg/week.
- Circulating LErafAON was detectable at 24 hours in most patients at higher doses, and c-raf-1 mRNA suppression was observed in some.
Conclusions:
- Hypersensitivity reactions and thrombocytopenia limited LErafAON tolerability.
- The liposomal formulation demonstrated potential for AON delivery and target engagement, but modifications are necessary for future clinical development.
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