Purpose:To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between nont hermosensitive liposomes (NTSL) and low temperature^sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42jC for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.The dose of drug required to achieve clinically effective cytotoxicity in tumors often causes severe damage to actively propagating nonmalignant cells, resulting in a variety of undesirable side effects (1). Abnormal and heterogeneous distribution of inefficient vasculature (2), high interstitial fluid pressures (3), and fibrillar collagen in the extracellular matrix (4) are some of the barriers that further complicate effective and uniform drug delivery to tumors. Novel paradigms to overcome these barriers with new drug and device combinations may present fertile ground for continued research.Employing drug delivery strategies, such as liposomal encapsulation, can optimize and enhance the delivery of different agents with lower systemic toxicity and better drug cell internalization compared with free drug (5). A smaller volume of distribution and prolonged clearance time may also be achieved by incorporating lipid-conjugated polyethylene glycol into the liposomal membrane. This polyethylene glycolylation provides a protective barrier against interactions with plasma proteins and the reticuloendothelial system, allowing for enhanced accumulation of the chemotherapeutic agent into tumors (6). Polyethylene glycolylated liposomes containing doxorubicin, or Doxil, have bee...

Purpose:To evaluate the influence of subtotal radiofrequency (RF) ablation on a tumor-specific immune response in a murine tumor model and to explore the role of intratumoral dendritic cells (ITDCs) in mediating this effect. Materials and Methods:Animal work was performed according to an approved protocol and in compliance with the National Cancer Institute Animal Care and Use Committee guidelines and regulations. A murine urothelial carcinoma (MB49) model expressing the male minor histocompatibility (HY) antigen was inoculated subcutaneously in female mice. Fourteen days later, splenic T cells were analyzed with enzymelinked immunosorbent spot for HY immune response (n ϭ 57). In subsequent experiments, mice were randomized into control (n ϭ 7), RF ablation, ITDC (n ϭ 9), and RF ablation ϩ ITDC (n ϭ 9) groups and monitored for tumor growth. Eleven days after treatment, tumors were harvested for histologic and immunohistochemical analysis. Animals demonstrating complete tumor regression were rechallenged in the contralateral flank. Results:Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY antigens and tumor regression. RF ablation, ITDC, and combined groups demonstrated similar levels of antigenpresenting cell infiltration; all groups demonstrated greater levels of infiltration compared with untreated controls. ITDC injection also resulted in tumor regression. However, combination therapy did not enhance tumor regression when compared with either treatment alone. Rechallenged mice in RF ablation, ITDC, and combination groups demonstrated significant tumor growth inhibition compared with controls. Conclusion:Subtotal RF ablation treatment results in enhanced systemic antitumor T-cell immune responses and tumor regression that is associated with increased dendritic cell infiltration. ITDC injection mimics the RF ablation effect but does not increase immune responses when injected immediately after RF ablation.

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PURPOSE A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD) (Celsion Corp., Columbia, MD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic (PK) properties, and dose limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS Subjects eligible for percutaneous or surgical RFA with primary (n=9) or metastatic (n=15) tumors of the liver, with lesions 4 or less in number and up to 7 cm in diameter were included. RFA was initiated 15 minutes after starting a 30 minute intravenous LTLD infusion. Dose levels between 20 and 60 mg/m2 were evaluated. MRI, PET and CT scans were performed at predetermined intervals pre and post-treatment until evidence of recurrence, administration of additional antitumor treatment, or a total of 3 years. RESULTS DLT criteria were met at 60 mg/m2, and the MTD was defined as 50 mg/m2. RFA was performed during the peak of the plasma concentration-time curve, in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSION LTLD can be safely administered systemically at the MTD (50 mg/m2) in combination with RFA, with limited and manageable toxicity. Further evaluation of this agent combined with RFA is warranted to determine its role in the management of liver tumors.

Introduction-Thrombotic disease continues to account for significant morbidity and mortality. Ultrasound energy has been investigated as a potential primary and adjunctive treatment for thrombotic disease. We have previously shown that pulsed-high intensity focused ultrasound (HIFU) enhances thrombolysis induced by tissue plasminogen activator (tPA) in vitro, including describing the non-destructive mechanism by which tPA availability and consequent activity is increased. In this study we aimed to determined if the same effects could be achieved in vivo.