Multifunctional Traceable Liposomes with Temperature-Triggered Drug Release and Neovasculature-Targeting Properties for Improved Cancer Chemotherapy.

Poor distribution of nanocarriers at the tumor site and insufficient drug penetration into the tissue are major challenges in the development of effective and safe cancer therapy. Here, we aim to enhance the therapeutic effect of liposomes by accumulating doxorubicin-loaded liposomes at high concentrations in and around the tumor, followed by heat-triggered drug release to facilitate low-molecular-weight drug penetration throughout the tumor. A cyclic RGD peptide (cRGD) was incorporated into liposomes decorated with a thermosensitive polymer that allowed precise tuning of drug release temperature (i.e., Polymer-lip) to develop a targeted thermosensitive liposome (cRGD-Polymer-lip). Compared with conventional thermosensitive liposomes, cRGD-Polymer-lip enhanced the binding of liposomes to endothelial cells, leading to their accumulation at the tumor site upon intravenous administration in tumor-bearing mice. Drug release triggered by local heating strongly inhibited tumor growth. Notably, tumor remission was achieved via multiple administrations of cRGD-Polymer-lip and heat treatments. Thus, combining the advantages of tumor neovascular targeting and heat-triggered drug release, these liposomes offer high potential for minimally invasive and effective cancer chemotherapy.

Multifunctional liposomes having target specificity, temperature-triggered release, and near-infrared fluorescence imaging for tumor-specific chemotherapy.

We designed functional liposomes with target specificity, temperature-triggered drug release, and near-infrared fluorescence imaging. We prepared the liposomes by triple functionalization of stable pegylated liposomes with thermosensitive poly[2-(2-ethoxy)ethoxyethyl vinyl ether] chains (lower critical solution temperature around 38 °C) with conjugation of antibody trastuzumab (Herceptin, HER), which targets human epidermal growth factor 2, and with incorporation of indocyanine green for near-infrared fluorescence imaging. The liposomes retained DOX in the interior below physiological temperature but released DOX immediately at temperatures higher than 40 °C. The liposomes exhibited excellent ability for association and internalization to target cells overexpressing Her-2, such as SK-OV3 and SB-BR3 cells, and killed these cells when heated at 45 °C for 5 min. When administered intravenously to mice bearing SK-OV3 tumor, the liposomes having HER accumulated in the tumor more efficiently than the liposomes without HER. They stayed there more than 48 h, as judged with near-infrared fluorescence imaging. Furthermore, when the tumor sites of the mice being administered with the DOX-loaded liposomes were heated mildly at 44°C for 10 min at 7h after administration, tumor growth was suppressed strongly thereafter. Treatment with the HER-conjugated liposomes produced more efficient tumor-suppressive effects. Results demonstrate that the synergy of target-specific association, temperature-triggered drug release, and imaging is important for efficient tumor chemotherapy.

PEGylated PAMAM dendrimer-doxorubicin conjugate-hybridized gold nanorod for combined photothermal-chemotherapy.

We prepared pH-sensitive drug-dendrimer conjugate-hybridized gold nanorod as a promising platform for combined cancer photothermal-chemotherapy under in vitro and in vivo conditions. Poly(ethylene glycol)-attached PAMAM G4 dendrimers (PEG-PAMAM) were first covalently linked on the surface of mercaptohexadecanoic acid-functionalized gold nanorod (MHA-AuNR), with subsequent conjugation of anti-cancer drug doxorubicin (DOX) to dendrimer layer using an acid-labile-hydrazone linkage to afford PEG-DOX-PAMAM-AuNR particles. The particles with a high PEG-PAMAM dendrimer coverage density (0.28 per nm(2) AuNR) showed uniform sizes and excellent colloidal stability. In vitro drug release studies demonstrated that DOX released from PEG-DOX-PAMAM-AuNR was negligible under normal physiological pH, but it was enhanced significantly at a weak acidic pH value. The efficient intracellular acid-triggered DOX release inside of lysosomes was confirmed using confocal laser scanning microscopy analysis. Furthermore, the combined photothermal-chemo treatment of cancer cells using PEG-DOX-PAMAM-AuNR for synergistic hyperthermia ablation and chemotherapy was demonstrated both in vitro and in vivo to exhibit higher therapeutic efficacy than either single treatment alone, underscoring the great potential of PEG-DOX-PAMAM-AuNR particles for cancer therapy.