From Combinatorial Chemistry to Cancer Targeting to Nanotherapeutics

October 23, 2009
Kit S. Lam M.D., Ph.D.
Professor of Medicine, Chief, Division of Hematology & Oncology, University of California, Davis


The one-bead-one-compound (OBOC) combinatorial library technology [1] enables us to generate millions of compound-beads, each with unique chemical compound displayed on the bead surface. When mixed with live cancer cells, compound-beads that bind to cancer cell surface receptors are coated with a monolayer of cancer cells. These cell-bound beads are then isolated for structure analysis, through either direct Edman sequencing or via chemical decoding. With this approach, peptide leads that interact with a number of different cancer cells and normal cells were identified.

We have recently developed a number of amphiphilic polymers, comprised of a cluster of cholic acids (4 to 10) linked by a series of lysines and attached to one end of a linear polyethylene glycol chain (PEG, 2000-5000 Dalton). Under aqueous condition, such telodendrimers can self-assemble to form highly stable nanomicelles [2]. This nanoplatform is multifunctional and highly versatile. We can readily load hydrophobic drugs, radionuclides, fluorochromes, quantum dots, and iron nanoparticles into the hydrophobic core of these nanomicelles. We can also conjugate cancer-targeting peptides to the distal end of the telodendrimer such that these peptides will be displayed on the surface of the final drug-loaded nanoparticles. The size of the final nanocarriers (15-150 nm diameter) and their drug loading capacity are tunable depending on the size of the PEG chain and the number and arrangement of cholic acid molecules in the dendrimer. We have also compared the therapeutic efficacy and toxicity profile of our paclitaxel-loaded nanomicelles with the two FDA approved formulations of paclitaxel (Taxol® and Abraxane®) in nude mice bearing ovarian cancer xenograft, and determined that the nanomicelles had superior anti-tumor effects and toxicity profile. Nanomicelles smaller than 64nm preferentially targeted xenografts with high efficiency and with low liver and lung uptake, whereas those nanomicelles at 154nm targeted the tumor poorly but with very high liver and lung uptake. When decorated with cancer targeting ligands identified from the one-bead-one-compound (OBOC) combinatorial library methods the drug-loaded nanoparticles were rapidly taken up by the target tumor cells causing cell death. These ligands include LLP2A, LXY3 and LXW7 that target the a4b1, a3b1, and avb3 integrins, respectively. In vivo near infra-red optical imaging studies with hydrophobic fluorescent dye demonstrated that xenograft uptake of the nanomicelles was greatly enhanced by the cancer targeting peptide. Confocal microscopy revealed that the targeted nanomicelles, unlike the naked nanomicelles, were distributed throughout the entire tumor mass and not just in the perivascular space.

[1] Lam KS, Salmon SE, Hersh EM, Hruby V, Kazmierski WM, Knapp RJ: A new type of synthetic peptide library for identifying ligand-binding activity. Nature 354(7):82-84, 1991.

[2] Xiao K, Luo J, Fowler W, Li Y, Lee JS, Xing L, Cheng RH, Wang L and Lam KS. A self-assembling nanoparticle for paclitaxel delivery in ovarian cancer. Biomaterial. 30:6006-6016, 2009.


Dr. Kit Lam was born in Hong Kong, obtained his B.A. in Microbiology in 1975 at the University of Texas at Austin. He obtained his Ph.D. in Oncology in 1980 from McArdle Laboratory for Cancer Research, University of Wisconsin, and his M.D. in 1984 from Stanford University School of Medicine. He completed his Internal Medicine residency training and Medical Oncology Fellowship training at the University of Arizona. He is board certified in both Internal Medicine and Medical Oncology. He was on the faculty of the University of Arizona until June 1999, when he joined UC Davis School of Medicine as the Division Chief of Hematology/Oncology, a position he continues to hold today. He is both a practicing medical oncologist and a laboratory investigator.

Dr. Lam invented the "one-bead one-compound" (OBOC) combinatorial library method, which was first published in Nature in 1991. The article has since been cited over 1,100 times. He is a founding scientist of the Selectide Corporation, one of the first start-up companies to specialize in combinatorial chemistry. He has published over 238 scientific publications and is an inventor on 12 patents.

His research encompasses the development and applications of combinatorial chemistry to basic research and drug development. On-going projects in his laboratory include the development of novel encoding techniques and screening methods for OBOC combinatorial libraries, development of cancer cell surface targeting agents for cancer therapy and in vivo imaging, development of novel nanotherapeutics, identification of substrates and development of inhibitors for protein kinases, protein tyrosine sulfotransferases and proteases, applications of OBOC combinatorial library methods and chemical microarrays for cancer proteomics and enzyme profiling, development of novel glyco-markers for cancer diagnosis, development of imaging and therapeutic agents for Alzheimer’s disease, and development of antiviral agents.