In the first half of my talk, I will discuss the design of drug-loaded nanoparticles of elastin-like polypeptides (ELPs) for systemic delivery of anti-cancer chemotherapeutics. ELPs are a class of artificial polypeptides �also called protein polymers� whose repeat unit is borrowed from a VPGXG motif that recurs in tropoelastin.  ELPs undergo a lower critical solution temperature transition, in which ELPs undergo phase separation in response to environmental variables such as an increase in temperature or salt concentration.  We have explored the capacity of ELPs to self-assemble into nanostructures in response to a range of stimuli. In one example, we designed a chimeric polypeptide that consists of two segments: (VPGXG)n repeats followed by a short (GGY)n segment, and showed that attachment of multiple copies of a hydrophobic molecule at the Y position can impart sufficient amphiphilicity to the polypeptide and thereby drive its self-assembly into near-monodisperse nanoparticles with the attached hydrophobic small molecule embedded in the core of the nanoparticle.  This is an interesting finding, because it appears that any molecule with a hydrophobicity that is greater than a threshold value appears to drive attachment-triggered self-assembly of the chimeric polypeptide into a nanoparticle.  Because many cancer chemotherapeutics are insoluble hydrophobic small molecules with poor bioavailability, this approach of attachment-triggered encapsulation of small hydrophobic molecules into soluble nanoparticles has great utility to increase the solubility, plasma-half-life and tumor accumulation of cancer chemotherapeutics.   I will demonstrate the efficacy of this approach with two cancer drugs, doxorubicin and paclitaxel.The second half of my talk talk will summarize two examples of ELPs that can be digitally switched between two states in response to a physiologically relevant trigger. In one example of the utility of ELPs for drug delivery, I will discuss the design of diblock ELPs that self-assemble into monodisperse micelles in response to a thermal trigger, wherein self-assembly in the narrow temperature range between 37 �C (normal body temperature) and 42 �C (highest temperature approved for mild clinical hyperthermia) results in the presentation of a functional cell penetrating peptide  (CPP) motif.  The presentation of a functional CPP only at 42 �C, but not at 37 �C opens the way to convert CPPs, which are powerful yet promiscuous agents to promote the uptake of drugs into cells, into an exquisitely targeted system for cancer drug delivery via the application of focused external hyperthermia to solid tumors. In the second example, I will describe the design of the first pH-responsive polypeptide micelle that dissociates in response to the low extracellular pH of solid tumors.  This system consists of a histidine-rich diblock ELP that self-assembles at 37�C into spherical micelles that are further stabilized by Zn2+ and are disrupted as the pH drops from 7.4 to 6.4.  These pH-sensitive micelles demonstrate better in vivo penetration and distribution in tumors than a pH-insensitive control and provide a potential solution to the problem of limited tumor penetration of nanoparticle drug delivery vehicles. These examples illustrate the precision with which genetic engineering can be exploited for the design of peptide polymers that digitally switch between an assembled and disassembled state in response to a clinically relevant trigger, with intriguing implications for the in vivo delivery of drugs or imaging agents.

Genetically encoded polypeptide nanoparticles for delivery of drugs

247th National Meeting (2014)

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