Pathogenesis of Hand-Foot Syndrome induced by PEG-modified liposomal Doxorubicin

Abstract

PEGL-DOX is an excellent treatment for recurrent ovarian cancer that rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in Hand-Foot Syndrome (HFS). In severe cases, it can become necessary to reduce the PEGL-DOX concentration or the duration of the drug therapy, sometimes making it difficult to continue treatment. In this study, we prepared an animal model to compare the effects of DOX versus PEGL-DOX, and we noticed that only treatment with PEGL-DOX resulted in HFS, which led us to conclude that extravasation due to long-term circulation was one of the causes of HFS. In addition, we were able to show that the primary factor leading to the skin-specific outbreaks in the extremities was the appearance of reactive oxygen species (ROS) due to interactions between DOX and the metallic Cu(II) ions abundant in skin tissue. ROS directly disturb the surrounding tissue and simultaneously induce keratinocyte-specific apoptosis. Keratinocytes express the thermoreceptor TRPM2, which is thought to be able to detect ROS and stimulate the release of chemokines (IL-8, GRO, Fractalkine), which induce directed chemotaxis in neutrophils and other blood cells. Those cells and the keratinocytes then undergo apoptosis and simultaneously release IL-1β, IL-1α, and IL-6, which brings about an inflammatory state. In the future, we plan to develop preventative as well as therapeutic treatments by trapping the ROS.

Skin toxicity in a patient with ovarian cancer treated with pegylated liposomal doxorubicin: A case report and review of the literature

“…Jacobi et al (14) reported the appearance of PPE only in patients with hyperhidrosis of these regions. Another hypothesis is that PPE develops due to an excessive concentration of toxic doxorubicin within the skin and its reaction with metal ions (particularly copper ions) (15). An underlying mechanism for the development of other skin disorders is poorly known.…”

Aptamer–drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity

“…The pegylated liposome-encapsulated DOX form has low cardiotoxicity, but high skin and oral toxicity (hand-foot syndrome [HFS]) are induced partly because of extravasation of the liposomes due to long circulation time. 4,5 Therefore, in addition to pegylated liposome-encapsulated form of DOX, the use of non-pegylated liposomal (NPL)-DOX is also predominant in chemotherapy. 6 NPL-DOX as a component of the R-CHOP regimen is a highly effective treatment in patients with diffuse large B cell lymphoma and pre-existing cardiac diseases.…”

“…25 The HFS is partly caused by extravasation of the liposomes due to long circulation time. 5 The presence of targeting aptamer in our ApDC system could probably reduce the nonspecific circulatory time and enhance the tumor distribution and permeation, making it possible to reduce HFS symptoms compared to pegylated liposome-encapsulated DOX.…”

Nanomedicinal products: a survey on specific toxicity and side effects

“…For example, the reduced nephrotoxicity of liposomal amphotericin B 30 and the reduced cardiotoxicity of pegylated liposomal doxorubicin 37 are reflected in the reported side effects, as is the occurrence of hand-foot syndrome because of the pegylation of doxorubicin. 35 The reduced cardiotoxicity of liposomal daunorubicin has not been confirmed in comparative clinical trials but is supposed to be present based on other liposomal studies for anthracyclines. 15 The lower toxicological profile of liposomal cytarabine compared to conventional cytarabine could not be confirmed.…”

“…The difference in reporting between pegylated liposomal and conventional doxorubicin is mainly caused by the hand-foot syndrome (palmar-plantar erythrodysesthesia) including neuropathy, which is a side effect of multiple chemotherapeutic agents, but more so for PEG-modified liposomal chemotherapeutic preparations. 35 Overall, there are certain specific side effects associated with pegylated doxorubicin compared to regular doxorubicin, of which some can be related to the properties of the nanoformulation. In addition to the hand-foot syndrome for PEG-modified chemotherapeutics mentioned earlier, pegylated therapeutics can also cause unexpected immunemediated side effects.…”