Nanotechnologies have the potential to improve cancer therapy. In particular, liposomes and micelles serve as nano-sized drug delivery carriers for the administration of cancer drugs. Although micelles have not been approved by the Food and Drug Administration (FDA) in USA, some liposomal drugs have been already approved for use in anticancer therapy. In most cases, these liposomal drugs have improved pharmacokinetics and reduced side effects due to the encapsulation of the drug. Also, passive targeting to the tumor can be achieved due to physiological properties that lead to the enhanced permeability and retention (EPR) effect in tumor tissue. More recently, modification of the liposomal surface with active targeting molecules such as antibodies or natural receptor ligands has been investigated in clinical trials. Moreover, novel strategies for drug release, activation, and delivery with physical stimuli have been developed. There is a plethora of preclinical and clinical data about liposomal drugs for cancer therapy because they have been utilized as commercially available drugs for a long time. In the present review, we summarize the use of tumor-targeting technologies and approved liposomal antitumor drugs, describe their properties, and assess applications and challenges of liposome technologies for advanced cancer therapy.
Encapsulating anticancer drugs in liposomes improves their therapeutic window by enhancing antitumor efficacy and reducing side effects. To devise more effective liposomal formulations for antitumor therapy, many research groups have tried to develop tumor-targeting liposomes with enhanced drug release. Previously, we developed doxorubicin (Dox)-encapsulated AG73 peptide-modified liposomes (AG73-Dox), which targeted cancer and endothelial cells, and ultrasound (US) imaging gas-entrapping liposomes, called "Bubble liposomes" (BLs). In this study, to enhance the antitumor effect of AG73-Dox, we combined AG73-Dox with BLs and US. First, to determine whether the addition of BLs and application of US could enhance the cytotoxicity of AG73-Dox, we evaluated the cytotoxicity of the combination of AG73-Dox with BLs and US. BLs and US enhanced cytotoxicity of AG73-Dox more than they enhanced nontargeted Dox-encapsulated liposomes. Next, we examined the intracellular behavior of Dox after treatment with BLs and US. The combination of AG73-Dox with BLs and US did not enhance cellular uptake of Dox, but it did promote drug release in the cytoplasm. To further elucidate the release of Dox in the cytoplasm, we blocked cellular uptake via endosomes at a low temperature. As a result, BLs and US did not have an enhanced drug-release effect until AG73-Dox was taken up into cells. Thus, the combination of AG73-Dox with BLs and US may be useful for cancer therapy as a dual-function drug delivery system with targeted and controlled release.
Abstract OBJECTIVE In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat. METHODS The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images. RESULTS The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage. CONCLUSIONS Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.
