Tumour eradication using synchronous thermal ablation and Hsp90 chemotherapy with protein engineered triblock biopolymer-geldanamycin conjugates.
OBJECTIVE
Hepatocellular carcinoma (HCC) suffers high tumour recurrence rate after thermal ablation. Heat shock protein 90 (Hsp90) induced post-ablation is critical for tumour survival and progression. A combination therapy of thermal ablation and polymer conjugated Hsp90 chemotherapy was designed and evaluated for complete tumour eradication of HCC.


METHODS
A thermo-responsive, elastin-like polypeptide (ELP)-based tri-block biopolymer was developed and conjugated with a potent Hsp90 inhibitor, geldanamycin (GA). The anti-cancer efficacy of conjugates was evaluated in HCC cell cultures with and without hyperthermia (43 °C). The conjugates were also administered twice weekly in a murine HCC model as a single treatment or in combination with single electrocautery as the ablation method.


RESULTS
ELP-GA conjugates displayed enhanced cytotoxicity in vitro and effective heat shock inhibition under hyperthermia. The conjugates alone significantly slowed the tumour growth without systemic toxicity. Four doses of thermo-responsive ELP-GA conjugates with concomitant simple electrocautery accomplished significant Hsp90 inhibition and sustained tumour suppression.


CONCLUSIONS
Hsp90 inhibition plays a key role in preventing the recurrence of HCC, and the combination of ablation with targeted therapy holds great potential to improve prognosis and survival of HCC patients.
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah , Salt Lake City .
Yizhe
Y
Chen
Pilju
P
Youn
Theodore J
TJ
Pysher
Courtney L
CL
Scaife
Darin Y
DY
Furgeson
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D016227:Benzoquinones / Q000008:administration & dosage* / Q000737:chemistry; D001704:Biopolymers; D015153:Blotting, Western / Q000379:methods; D017115:Catheter Ablation / Q000379:methods; D003131:Combined Modality Therapy / Q000379:methods; D004337:Drug Carriers; D005434:Flow Cytometry / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000737:chemistry; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry*; D015202:Protein Engineering
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D001704:Biopolymers; D004337:Drug Carriers; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010455:Peptides; C033943:elastin polypentapeptide; C001277:geldanamycin
Combination therapy; elastin-like polypeptide; heat shock protein 90; hepatocellular carcinoma; thermal ablation