PEGylated as opposed to non-PEGylated liposomes can have beneficial effects when it comes to delivering drugs. PEGylated liposomes have been shown to have a longer half-life or circulation time and may be able to target different tissues due to its varied distribution in the body. Two different PEGylated Doxorubicin liposomes have gone to clinical trials, Doxil™ and Lipo-dox™. We will briefly discuss the two forms of PEGylated doxorubicin on the market below.
Doxil™ owned and marketed by Janssen (a subsidiary of Johnson & Johnson)
Doxil™ consists of hydrogenated soy phosphatidycholine (HSPC), cholesterol (CH), & polyethyleneglycol 2000-distearoylphosphatidylethanolamine (PEG-2000-DSPE); HSPC:CH:PEG-2000-DSPE 56:39:5 molar ratio. Liposome preparations are sized to around 100nm.
Pharmacokinetic studies showed that the PEGylated Doxorubicin liposomes had significantly longer circulation time as opposed to non-PEGylated Doxorubicin (Myocet™) liposomes and free Doxorubicin. The prolonged circulation time is most likely due the inhibition of interactions with plasma proteins and mononuclear phagocytes. Comparing the elimination half-life of free Doxorubicin, Myocet™ , and Doxil™ (0.2 hours, 2.5 hours and 55 hours respectively) it is clear to see that the PEGylated liposomes have a significantly longer circulating time. Furthermore it was reported that the area under the plasma concentration of free Doxorubicin, Myocet™ , and Doxil™ was 4µg h mL-1, 45µg h mL-1 and 900µg h mL-1 respectively.
In phase III studies comparing Free Doxorubicin Drug to PEGylated Doxorubicin (Doxil™) liposomes a reduction in incidence of cardiotoxicity at an 3.9% as opposed to 18.8% was seen respectively. Moreover, Doxil™ showed lowered occurrences of other side effects in relation to Myocet™, the factors studied included effects such as alopecia (20% vs. 66%), vomiting (19% vs. 31%) and neutropenia (4% vs. 10%). Unfortunately while Doxil™ showed lower occurrences of problematic adverse effects seen with free Doxorubicin and liposomal non-PEGylated Doxorubicin, other dose-limiting factors arose. The harshest among these side effects was palmar-plantar erythrodysesthesia also known as hand-foot syndrome. In a study comparing free Doxorubicin to Doxil™ it was found that Doxil™ showed a higher incidence of palmar-plantar erythrodysesthes (48% vs. 2%), stomatitis (22% vs. 15%) and mucositis (23% vs. 13%).
While the side effects of PEGylated liposomal Doxorubicin were lower than the conventional treatment of Doxorubicin the antitumor effects proved to be equivalent. This was measured as both progression-free survival time and overall survival time. Discouragingly side effects such as stomatitis, mucositis, and palmar-plantar erythrodysesthesia occurred more often in the subjects receiving Doxil™.
Lipo-dox™ owned and marked by Taiwan Liposome Company
Lipo-dox™ consisted of distearoylphosphatidylcholine (DSPC), cholesterol (CH), & polyethylene glycol 2000-distearoylphosphatidylethanolamine (PEG-2000-DSPE); DSPC:CH:PEG-2000-DSPE 56:39:5 molar ratio. Liposome preparations are sized to around 100nm.
Lipo-dox™ showed much of the same profile as did Doxil™. Overall progression and survival time were consistent with patients receiving free Doxorubicin even though Lipo-dox™ achieved the highest circulation time of 65 hours. Lipo-dox™ proved to be more stable than Doxil™ due to the properties of DSPC. Distearoylphosphatidylcholine (DSPC) is a saturated fatty acid, with uniform acyl chain length and a high phase-transition temperature of 55oC. Moreover, skin toxicity, neutropenia and stomatitis were reported at significant rates. Stomatitis became so severe in subjects that it became the dose-limiting factor as opposed to cardiotoxicity in non-PEGylated liposomal Doxorubicin.
Copyright by Encapsula NanoSciences 2014
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