title: Thermo-targeted drug delivery of geldanamycin to hyperthermic tumor margins with diblock elastin-based biopolymers.
abstract: The tumor margins are the barrier to hepatocellular carcinoma (HCC) eradication for tumors>3 cm. Indeed, inadequately treated tumor margins commonly result in local and regional HCC recurrence with increased size and mass. Tumor recurrence is a common problem with chemotherapy, radiotherapy, thermal ablation, and/or surgical resection, by the inability to properly treat the tumor core and the tumor margins. Here we present novel thermosensitive biopolymer-drug conjugates for thermo-targeted chemotherapy at hyperthermic isotherms produced by focal, locoregional thermal ablation. The chemotherapeutic target is heat shock protein 90 (HSP90), a key molecular chaperone of several, and potent pro-oncogenic pathways including Akt, Raf-1, and mutated p53 that is upregulated in HCC. To inhibit HSP90, we have chosen geldanamycin (GA), a potent HSP90 inhibitor. GA has gained significant attention for its low IC50 ~ 1 nM and inhibition of Akt and Raf-1, amongst other critical pro-oncogenic pathways. Despite such evidence, clinical trials of GA have not shown promise due to off-target toxicity and poor formulation design. Here, we propose using diblock elastin-based biopolymers as a Ringsdorf macromolecular GA solubilizer--a new generation containing functional poly(Asp)/(Glu) blocks for facile drug conjugation and an ELP block for thermo-targeting of hyperthermic ablative margins. GA release is controlled by pH-sensitive, covalent hydrazone bonds with the biopolymer backbone to avoid systemic toxicity and off-target effects. The resultant biopolymer-conjugates form stable nanoconstructs and display tunable, acute phase transitions at high temperatures. Drug release kinetics are favorable with or without the presence of serum. Thermo-targeted chemotherapy and synchronous thermal ablation provide a unique opportunity for simultaneous destruction of the HCC ablative margins and tumor core for focal, locoregional control of HCC.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108–3549, USA. yizhe.chen@utah.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: Pilju
authors.initials: P
authors.lastname: Youn
authors.forename: P
authors.initials: P
authors.lastname: Youn
authors.forename: Darin Y
authors.initials: DY
authors.lastname: Furgeson
authors.forename: D Y
authors.initials: DY
authors.lastname: Furgeson
mesh_terms: D055011:Ablation Techniques; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D016227:Benzoquinones / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004549:Elastin / Q000737:chemistry* / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006358:Hot Temperature; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry* / Q000235:genetics; D010316:Particle Size; D044367:Phase Transition; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013302:Streptomyces / Q000235:genetics; D013499:Surface Properties; D044366:Transition Temperature
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004337:Drug Carriers; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009841:Oligonucleotides; D004549:Elastin; C001277:geldanamycin