Enhanced Antitumor Efficacy and Reduced Systemic Toxicity of Sulfatide-Containing Nanoliposomal Doxorubicin in a Xenograft Model of Colorectal Cancer

Abstract

Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX), a sulfatide-containing liposome (SCL) encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX) using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach

“…Moreover, this effect was visible at concentrations approximately two- to threefold lower than that of the free drug. This is in agreement with previous studies that demonstrated a remarkable enhancement of the cytotoxic actions of DOX when included in liposomes, nanoparticles or other lipid-based formulations 66–70. To enhance the efficacy of DOX for further in vivo studies, we designed two liposomal formulations based on the co-encapsulation of DOX and CUR.…”

Anticancer activity of galactoxyloglucan polysaccharide-conjugated doxorubicin nanoparticles: Mechanistic insights and interactome analysis

“…The favorable properties exhibited by PST-Dox nanoparticles in terms of increased cancer specific cytotoxicity and minimal toxicity towards normal cells could be attributed to the higher intracellular accumulation and deeper penetration of the nanoparticles into the cancer cells. The anthracycline doxorubicin's delivery to tumor cells is sub-optimal in its unmodified form, creating wide distribution and delivery of the drug at untargeted regions, and hence, severe side effects are expected [31]. Earlier in vivo studies have proved the tumor-specific accumulation of the PST-Dox nanoparticles both in ascites and solid tumors [19].…”

Improved Efficacy and Reduced Toxicity of Doxorubicin Encapsulated in Sulfatide-Containing Nanoliposome in a Glioma Model

“…This difference could largely be attributed to the fact that in the current study, the biodistribution study in tumor-bearing mice was performed after 6 injections of 5 mg/kg of DOX or SCN-DOX over a 6 week period while in our previous study the biodistribution study was performed after a single injection [35].Repeated injections of liposomal formulation are known to alter the PK of therapeutic agents [64]. Thus, the difference in tissue concentrations of DOX and SCN-DOX between animals receiving a single injection [35] and multiple injections (this study) might be resulted from the profoundly altered pharmacokinetic behaviour of the same agent after multiple administrations.…”