Controlled and targeted tumor chemotherapy by micellar-encapsulated drug and ultrasound.
The results of a comprehensive in vivo study of a novel tumor-targeting modality are reported. The technique utilized in this study is based on the encapsulation of the chemotherapeutic agent within polymeric micelles in combination with a local ultrasonic irradiation of the tumor. A doxorubicin (DOX) biodistribution, a yield of the internal tumors and a growth rate of the subcutaneous (s.c.) tumors was compared for molecularly dissolved and micellar-encapsulated DOX. This was done with and without tumor sonication, using an ovarian carcinoma tumor model in nu/nu mice. Pure and mixed Pluronic P-105, PEG2000-diacylphospholipid, and poly(ethylene glycol)-co-poly(beta-benzyl-L-aspartate) micelles were used as drug carriers. DOX intracellular uptake was characterized by flow cytometry. A local ultrasonic irradiation of the tumor resulted in a substantially increased drug accumulation in the tumor cells. The effect of the ultrasound was dependent on the time between ultrasound application and drug injection. Ultrasound did not enhance micelle extravasation; the ultrasonic enhancement of drug internalization by the tumor cells required a preliminary passive drug accumulation in the tumor interstitium. Due to the ultrasound-enhanced drug intracellular uptake and cell killing, the yield of intraperitoneal (i.p.) ovarian carcinoma tumors decreased from 70% for DOX dissolved in PBS (positive control) to 36% for the same concentration of DOX encapsulated in Pluronic micelles combined with a 30-s sonication of the abdominal region of a mouse (3 mg/kg DOX, i.p. injection 1 day after inoculation, n>or=10). For s.c. tumors, micellar delivery combined with localized ultrasonic tumor irradiation resulted in a substantial decrease of the tumor growth rates compared to a positive control (3 mg/kg DOX, i.v. injections, n=7, p<0.05). Possible mechanisms of the ultrasound bioeffects on in vivo drug targeting are discussed.
Gao
Zhong-Gao
ZG
Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
Fain
Heidi D
HD
Rapoport
Natalya
N
D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D014464:Ultrasonic Therapy / Q000379:methods*
D003692:Delayed-Action Preparations; D008823:Micelles