Targeting CD37 and folate receptor for cancer therapy : strategies based on engineered protein and liposomes. (2007)

One of the lingering challenges in cancer therapy is to selectively destroy malignant cells and minimize the toxicity to normal tissues.The field of therapeutic targeting has thus been attractive with the ultimate goal of developing anti-cancer agents that work like "magic bullets".Herein, we explore therapeutic approaches through targeting to CD37 and folate receptor, two promising cellular surface markers that can be utilized for antibody and liposome-based targeted therapies.In the first part, a novel recombinant CD37-targeted small modular immunopharmaceutical (CD37-SMIP) and nanoscale liposomal particles were used to target CD37 molecule.CD37 represents an attractive target for immunotherapy in B cell malignancies, but has been neglected in the past.We first demonstrated specific expression of CD37 surface antigen on B but not T cells in peripheral blood mononuclear cells (PBMC) from chronic lymphocytic leukemia (CLL) patients.Crosslinking the CD37 resulted in dose and time dependent apoptosis by CD37-SMIP in CLL B cells.In addition, CD37-SMIP induced antibody dependent cellular cytotoxicity (ADCC) but not completment dependent cytotoxicity (CDC) in CLL cells.In vivo therapeutic efficacy of CD37-SMIP was demonstrated in a Raji cell xenograft mouse model.These findings provide strong justification for CD37 as a therapeutic target and introduce SMIP as a novel class of targeted therapies for B cell malignancies.Furthermore, immunoliposomes specific to CD37 were constructed using post insertion method to validate the use of iii liposomes as a carrier to potentiate the effect of CD37-SMIP.CD37-immunoliposomes specifically bound to CD37 + cells and induced apoptosis without the need for a crosslinking secondary antibody, a mechanism different from that mediated by CD37-SMIP molecule.These data suggest that CD37-immunoliposomes can act as a novel formulation design for CD37-SMIP, and may also be utilized for delivery of therapeutic agents, such as chemotherapies and nucleic acid-based therapies.In the second part, folate receptor (FR) was investigated as a cellular target for liposomal delivery of chemotherapeutic and radiation therapeutic agents.In the first study, cholesterol derivatives, PEG-cholesterol and folate-PEG-cholesterol, were synthesized for PEGylation and FR targeting.These two compounds were incorporated into the lipid bilayer of FR-targeted liposomal doxorubicin.The physicochemical properties, binding affinity as well as in vivo circulation of these particles were investigated.These studies suggested that cholesterol is a viable bilayer anchor for synthesis of FR-targeted liposomes.In addition, liposomes have been a main focus of tumor selective boron delivery strategies in boron neutron capture therapy (BNCT).Three novel carboranyl cholesterol derivatives were incorporated into the lipid bilayer components for the construction of FR-targeted boronated liposomes for BNCT.These liposomes were taken up extensively in FR overexpressing KB cells in vitro and the uptake was effectively blocked in the presence of free folate.These data collectively suggest that FR-targeted liposomes can be used as a delivery strategy for this class of novel carboranyl cholesterol derivatives.