Tumor‐targeted intracellular delivery of anticancer drugs through the mannose‐6‐phosphate/insulin‐like growth factor II receptor

Abstract

Tumor-targeting of anticancer drugs is an interesting approach for the treatment of cancer since chemotherapies possess several adverse effects. In the present study, we propose a novel strategy to deliver anticancer drugs to the tumor cells through the mannose-6-phosphate/insulin-like growth factor receptor (M6P/IGF-IIR) which are abundantly expressed in several human tumors. We developed a drug carrier against M6P/IGF-II receptor by modifying human serum albumin (HSA) with M6P moieties. M6P-HSA specifically bound and internalized into M6P/IGF-IIR-expressing B16 melanoma cells as demonstrated with radioactive studies and anti-HSA immunostaining. In vivo, M6P-HSA rapidly accumulated in subcutaneous tumors in tumor and stromal components after an intravenous injection. To demonstrate the application of M6P-HSA as a drug carrier, we coupled doxorubicin to it. Dox-HSA-M6P conjugate could release doxorubicin at lysosomal pH and showed M6P-specific binding and uptake in tumor cells. In vitro, a short exposure with Dox-HSA-M6P induced killing of tumor cells, which could be blocked by excess M6P-HSA. In vivo, Dox-HSA-M6P distributed to tumors and some other organs while free doxorubicin distributed to all organs but slightly to tumors. In B16 tumor-bearing mice, Dox-HSA-M6P significantly inhibited the tumor growth whereas an equimolar dose of free doxorubicin did not show any anti-tumor effect. In addition, targeted doxorubicin did not show any side-effects on liver and kidney function tests, body weight and blood cell counts. In conclusion, M6P-HSA is a suitable carrier for delivery of anticancer drugs to tumors through M6P/IGF-IIR. Improved antitumor effects of the targeted doxorubicin by M6P-HSA suggest that this novel approach may be applied to improve the therapeutic efficacy of anticancer drugs.

Biological Functionalization of Drug Delivery Carriers To Bypass Size Restrictions of Receptor-Mediated Endocytosis Independently from Receptor Targeting

“…44–46 Indeed, several therapeutic strategies (both experimental and already in the clinics) are based on M6PR targeting. 41,44–51 …”

“…43,44,46,47 and is often used for intracellular transport of therapeutics. 41,48–51 Also, there is relatively high expression of TfR associated with various malignancies, it allows transport across the blood-brain barrier, and has been well documented in the context of targeted drug delivery. 42,69,70 An example of an application of targeting these receptors is that of enzyme replacement therapies for treatment of genetic lysosomal storage disorders, where recombinant lysosomal enzymes are injected in circulation and need to be endocytosed by cells in the affected tissues.…”

Tetraiodothyroacetic acid-tagged liposomes for enhanced delivery of anticancer drug to tumor tissue via integrin receptor

“…In case of targeting moiety-modified nanoparticles, the distribution levels to other organs are still substantial. A recent study reported that 50% of albumin modified with mannose-6-phosphate as a targeting moiety was found to distribute to the liver, with less than 5% of the dose reaching the tumor tissue [42]. Moreover, some targeting moieties on nanoparticles can even enhance the distribution to the liver.…”

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

“…In follow-up studies, M6P-HSA was conjugated to several drugs with anti-proliferative or antifibrotic potential, including doxorubicin, mycophenolic acid, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) and so forth. (see also Table 1 ) [ 127 , 128 , 129 ]. All drug conjugates demonstrated superior antifibrotic activity in vivo compared to systemic application of their unconjugated counterparts.…”