Long-circulating delivery of bioactive polysaccharide from radix ophiopogonis by PEGylation

Abstract

Background: Radix ophiopogonis polysaccharide (ROP) has been found to be effective against myocardial ischemia. One of main problems with its use is its short in-vivo half-life, which makes the development of an effective delivery system necessary. To achieve better therapeutic effects and patient compliance by prolonging its retention in plasma and increasing its distribution in targets, ROP was PEGylated (PEG, polyethylene glycol) in this study. Methods: Through a moderate coupling reaction between hydroxyl-activated ROP and aminoterminated methoxy-PEG (mPEG) (30 or 40 kDa), together with a greater than 1 molar ratio of ROP to mPEG in reaction, long-circulating and potentially bioactive PEGylated ROPs, with PEG grafting number of ∼1.0, were prepared, characterized, and the pharmacokinetics evaluated. Results: Relative to ROP, whose half-life was approximately 0.7 hours, the two conjugates prepared, following intravenous administration, showed markedly prolonged retention in systemic circulation with half-lives in blood of 78.4 and 88.3 hours, respectively. When given subcutaneously, their in-vivo mean residence times were further markedly prolonged by the slow absorption phase. They were found to be well absorbed after subcutaneous administration, with absolute bioavailability being 75.4% and 43.9%, respectively. Conclusion: With apparent molecular masses not exceeding 43 kDa, the conjugates prepared have been and will be demonstrated to have prominent advantages for ROP delivery, such as: the good absorption following subcutaneous, intramuscular, or other ways of administration; the effective utilization of the enhanced permeability and retention effect caused by ischemia; and the rapid diffusion within target tissues.

Increased cardiac distribution of mono-PEGylated Radix Ophiopogonis polysaccharide in both myocardial infarction and ischemia/reperfusion rats

“…In comparison, liposomes (~100 nm) displayed slower and more restricted extravasation from the vasculature and are therefore an attractive vehicle for the delivery of proangiogenic drugs. 29 In the present research, the PEG-ROP conjugates, with a hydrodynamic size approximately or beyond 10 nm, 21 were studied in parallel on the rat models of both MI and IR to clarify their ability to accumulate in the ischemic myocardia via the EPR effect. …”

“…Permanent ligation and transient ligation of the left coronary artery were adopted to induce the aforementioned two clinically relevant pathological statuses of myocardial ischemia in rats, respectively. To determine the effect of the molecular size of conjugates, two representative conjugates (ie, 20-and 40-kDa PEG mono-modified ROPs), whose values are around the midpoint and the upper inflection point of the sigmoidal-shaped profile of plasma half-lives versus apparent molecular weights, respectively, 21 were studied in parallel at three time points postdose after a sensitive and specific method for determining them quantitatively in biosamples was established.…”

“…The reported glomerular filtration thresholds for PEG alone and PEGylated ROP were approximately 30 kDa 39,40 and 25.4 kDa, 21 respectively. The smaller threshold value for PEGylated ROP was believed to be due to its more spherical shape as well as lower flexibility and deformability in blood than the linear PEG agent alone.…”

The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles

“…[18][19][20][21] Here, we designed a novel investigation method to intensively research the widely used PEGylation strategy. Kataoka and colleagues [22][23][24] reported that polyion complex (PIC) micelles prepared from polymers with opposite charges were efficient nanocarriers for drug delivery.…”

Injectable long-acting systems for Radix Ophiopogonis polysaccharide based on mono-PEGylation and in situ formation of a PLGA depot

“…Injectable long-acting systems for radix Ophiopogonis polysaccharide for polymeric conjugation because of its unique advantages: 22 little antigenicity, immunogenicity, and toxicity; high solubility in many solvents; highly hydrated and flexible backbone; and approval by the US Food and Drug Administration for human use in injectables. PEG and its conjugates are cleared from the body mainly by the kidney, and the excretion rate has a sigmoidal relationship with the molecular weight of the polymer, showing a greatly reduced rate over approximately 40 kDa.…”