Biomaterials and nanomedicines are hot topics both in industry and in academia. Inspired by the self-assembly into hydrogels of hybrid water-soluble copolymers grafted with complementary natural motifs (pepticles or oligonucleoticles) we designed a new therapeutic paradigm for the treatment of CD20 positive B-cell lymphomas (CD20 is a non-internalizing receptor). This design is based on the unique phenomenon that crosslinking of CD20 receptors on the B cell surface mediates B cell apoptosis. This presentation will provide an excellent example that demonstrates similarities in the design of biomaterials and of macromolecular therapeutics. Most intriguingly, unlike nanomedicines consisting of drug/toxin and inert polymer carrier, in this new design the graft N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer performs complex biological functions in vivo via biorecognition of a pair of complementary pepticles or oligonucleoticles, and there is no drug/toxin involved. This new strategy is depicted in Fig. 1. The system is composed of two nanoconjugates: (a) anti-CD20 Fab' fragment covalently linked to a biological moiety (oligopeptide or oligonucleotide); (b) polyHPMA grafted with multiple copies of the complementary oligopeptide/oligonucleotide. Exposure of human non-Hodgkin lymphoma (NHL) Raji B cells to anti-CD20 Fab'-Motif 1 decorates the cell surface with pepticles/oligonucleoticles; further exposure of the decorated cells to graft copolymer P-(Motif 2)x results in the heterodimerization or hybridization, triggers crosslinking of CD20 receptors and initiates apoptosis in vitro and in a NHL animal model in vivo. Figure 1. Cartoon of overall design and possible mechanism of Drug-free Macromolecular Therapeutics (DFMT) for treatment of NHL. The induction of apoptosis in human Burkitt's NHL Raji B cells was triggered by crosslinking of the surface CD20 antigen due to biorecognition processes of antigen-antibody and complementary motifs. MRI and flow cytometry analysis indicated that no residual cancer cells were detectable in long-term survivors (125 days). Multimodality imaging studies investigating the interaction between cellular membranes and nanoconstructs, confirmed that self-assembly plays a critical role in this highly specific therapeutic systeml. Furthermore, DFMT demonstrated activity in the treatment of cells isolated from patients with chronic lymphocytic leukemia and mantle cell lymphoma, which suggests this highly as well as other B-cell derived hematologic neoplastic diseases and autoimmune disorders. Figure 2. Drug-free Macromolecular Therapeutics: a breakthrough in the treatment of B-cell malignance and autoimmune diseases.
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