Dissertation/Thesis Abstract

Targeting CD37 and Folate Receptor for Cancer Therapy: Strategies Based on Engineered Proteins and Liposomes
by Zhao, Xiaobin, Ph.D., The Ohio State University, 2007, 314; 10835896
Abstract (Summary)

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. We first demonstrated specific expression of CD37 surface antigen on B but not T cells. 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 but not complement dependent cytotoxicity 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 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. 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.

In the second part, folate receptor (FR) was investigated as a cellular target for liposomal delivery. In the first study, 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 study suggested that cholesterol is a viable bilayer anchor for synthesis of FR-targeted liposomes. In addition, FR-targeted liposomes were used to incorporate three novel carboranyl cholesterol derivatives for tumor selective delivery in boron neutron capture therapy (BNCT). Results from this study collectively suggest that FR-targeted liposomes can be used as a delivery strategy for this class of novel carboranyl cholesterol derivatives.

Indexing (document details)
Advisor: Lee, Robert
Commitee:
School: The Ohio State University
Department: Pharmacy
School Location: United States -- Ohio
Source: DAI-B 79/09(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology
Keywords: Cancer, Cd37, Folate receptor, Liposome, Monoclonal antibody, Targeted therapy
Publication Number: 10835896
ISBN: 9780355970531
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