Abstract_Lam Kit S. _15 Dec

advertisement
From Combinatorial Chemistry to Nanotheranostic Agents against Cancer
Kit S. Lam, M.D., Ph.D.
Professor and Chair
Department of Biochemistry & Molecular Medicine
Professor of Hematology & Oncology
Harold Albin Johnson Endowed Chair in Biomedical Research
University of California Davis
USA
Email:kslam@ucdavis.edu
Abstract
High-affinity high-specificity cell surface binding ligands can be discovered and optimized with "one-bead one-compound"
(OBOC) combinatorial library methods. In these experiments, live cells are mixed with OBOC chemical libraries and
positive beads coated by cells are isolated for structure determination. Using this approach, we have discovered LLP2A, a
peptidomimetic ligand that target activated α41 integrin, which is overexpressed in lymphoma cells. When conjugated to
CB-TE2A metal chelate and loaded with 64Cu, this ligand was found to target lymphoma xenografts with high specificity.
LXY30, an optimized cyclic peptide ligand against α31 integrin, which is overexpressed in several epithelial cancers, is
able to target both orthotopically and subcutaneously implanted glioblastoma xenografts with high efficiency. This cyclic
peptide ligand shows great promise as vehicle to deliver nanoparticle drugs or peptide toxins such as MMAE2 and for
cancer targeted therapy.
In addition to the discovery of cancer cell surface binding ligands, we have also adapted OBOC technology to the
discovery of cell penetrating peptides, peptides not only with high binding affinity and specificity but also with high
“endocytic” activities. We have developed OB2C technology to discover compounds that induce cell signaling or cell death.
A few years ago, we reported the use of Fmoc-chemistry to construct a number of amphiphilic polymers, comprised of a
cluster of cholic acids linked by a series of lysines and attached to one end of a linear polyethylene glycol chain. Under
aqueous condition, such telodendrimers self-assemble to form highly stable nanomicelles. This nanoplatform is
multifunctional and highly versatile. The size and surface charge of the final nanocarriers (15-150 nm diameter) are
tunable. We have demonstrated such paclitaxel-loaded nanoparticle drug outperforms the two FDA approved formulations
of paclitaxel (Taxol® and Abraxane®), in terms of efficacy and toxicity profile, in nude mice bearing ovarian cancer
xenograft. We have prepared 125I- radiolabeled and paclitaxel-loaded nanoparticles and demonstrated with SPECT/CT
scan that the nanoparticles retained preferentially in the xenograft implant for 4 days and with little uptake into liver and
lung. Cancer or blood vessel targeting peptides were ligated to the distal PEG end of the telodendrimer with click
chemistry. Such targeting nanoparticles can deliver the drug not only to the tumor site but also into the tumor cells,
making them more efficacious than nanoparticles without targeting peptides. To minimize premature drug release, we
have developed various strategies to reversibly stitch the telodendrimers together. Using electron paramagnetic
resonance and FRET studies, we demonstrated that non-crosslinked micelles are unstable when encounter lipoprotein
nanoparticles such as LDL, HDL, VLDL and chylomicron. Crosslinked nanoparticles, however, are stable in the presence
of these blood components and therefore clinically more efficacious. In addition to paclitaxel, we have also succeeded in
using this highly versatile nanoplatform to formulate many different drugs. These include etoposide, doxorubicin,
vincristine, SN-38, BCNU, temsirolimus, bortezomib, lapatinib, sorafenib and dexamethasone.
Recently, we reported in Nature Communication the use of a single polymer to develop a smart ‘all-in-one’ nanoporphyrin
platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins (NP) can be used as
amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI),
and dual modal PET-MRI. NPs greatly increase the imaging sensitivity for tumor detection through background
suppression in blood, as well as preferential accumulation and signal amplification in tumors. NPs also function as
multiphase nanotransducers that can efficiently convert light to heat inside tumors for photothermal therapy (PTT), and
light to singlet oxygen for photodynamic therapy (PDT). Furthermore, NPs act as programmable releasing nanocarriers for
targeted delivery of drugs or therapeutic radio-metals into tumors.
Li Y, Lin TY, Luo Y, Liu Q, Xiao W, Guo W, et al. A smart and versatile theranostic nanomedicine platform based on
nanoporphyrin. Nature Communications 2014; 5:4712. Epub 2014/08/27. doi: 10.1038/ncomms5712. PubMed PMID:
25158161; PubMed Central PMCID: PMC4145614.
Download