Center for Controlled Chemical Delivery

The Center for Controlled Chemical Delivery (CCCD) was established at the University of Utah in 1986 as a part of the State of Utah Centers of Excellence Program. CCCD is located in the Biomedical Polymers Research Building and consists of faculty from the Department of Pharmaceutics and Pharmaceutical Chemistry as core members and selected outside researchers. CCCD has attained a leading position worldwide in macromolecular therapeutics research and training of young scientists. Present collaborative projects include scientists from the Huntsman Cancer Institute, Department of Radiology, Cedar-Sinai Medical Center in Los Angeles, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Sichuan University, Chengdu, and University of Maryland.

Current research projects involve: a) Combination chemotherapy and immunotherapy of immunosuppressive cancers with polymer-drug conjugates and polymer – checkpoint inhibitor conjugates; b) Macromolecular therapeutics for brain delivery and treatment of primary central nervous system lymphoma and traumatic brain injury; c) Drug-free macromolecular therapeutics as a B-cell depletion strategy for various diseases; d) Crosslinking-mediated endocytosis; e) Design of new biomaterials a drug carriers.

The research in CCCD is supported by grants from the National Institutes of Health and Department of Defense, industry sponsored contracts, and intramural funds.

Research

Research in the Center for Controlled Chemical Delivery focuses on: a) Macromolecular therapeutics with emphasis on combination chemotherapy and immunotherapy; b) Macromolecular therapeutics for brain delivery; c) Drug-free macromolecular therapeutics – a new paradigm in nanomedicine where apoptosis is initiated by biorecognition of nanoconjugates at the cell surface and receptor crosslinking; no low molecular weight drug is needed.

Combination chemotherapy and immunotherapy

To develop methods for the treatment of immunosuppressive cancers we combine polymer-drug conjugates with polymer – checkpoint inhibitor conjugates. Newly designed backbone degradable HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer – anticancer drug conjugates possess long-circulating pharmacokinetics and enhanced antitumor activities, while keeping excellent biocompatibility. The conjugates induce immunogenic cell death in murine cancer models and convert “cold” tumors to “hot” ones that are susceptible to PD-L1 degradation immunotherapy. Original design of a new multivalent PD-L1 antagonist not only acts as a traditional checkpoint inhibitor, but mediates the surface crosslinking of PD-L1, biases its subcellular fate to lysosomes for degradation, and exhibits persistent suppression. Pre-clinical evaluation of the leading HPMA copolymer-epirubicin conjugate (KT-1) is being executed at the Nanotechnology Characterization Laboratory at NCI.

Macromolecular therapeutics for brain delivery

Nanomedicines designed for brain delivery/action have a difficult hurdle to overcome; they need to cross the blood brain barrier. We focus on receptor binding peptides that transcytose bound cargo into the brain. In particular, angiopep-2 (TFFYGGSRGKRNNFKTEEY) binds to LDLR (low-density lipoprotein receptor)-related protein (LRP)-1 followed by transcytosis. In collaboration with the Cedar-Sinai Medical Center in Los Angeles and the University of Utah Department of Radiology we are developing conjugates suitable for the treatment of central nervous system lymphoma, traumatic brain injury, and Alzheimer disease.

Drug-free macromolecular therapeutics (DFMT)

Our present studies evaluate the 2nd generation of DMFT. Anti-CD20 antibodies are divided into Type I such as rituximab (RTX) and Type II such as obinutuzumab (OBN); they have different patterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipid rafts, calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatible with homotypic adhesion regions, leading to actin cytoskeleton remodeling and lysosome disruption. Our design enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types of antibodies. This new system is composed of two nanoconjugates: a) bispecific engager, OBN-MORF1 (OBN conjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA-(MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholino oligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 to CD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA-(MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur. This new approach, called “clustered OBN (cOBN)” combines effects of both antibody types resulting in very high apoptotic levels.

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