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Immunogenic cell death (ICD) plays an important role in sensitizing tumor cells to antigen-presenting cells followed by antitumor immunity. However, a successful antitumor response by ICD requires both apoptotic tumor microenvironments and activated immune systems. Ivermectin (IVM) has been shown to induce cell apoptosis through autophagy which can be a great candidate for ICD therapy. However, a single treatment of IVM-free drug is not an ideal anticancer therapy due to its anti-inflammatory effects and cytotoxicity. In the present study, IVM was shown to enhance the ICD process in addition to the treatment of resiquimod (R848), a TLR7/8 agonist, when co-loaded in a squalene-based nanoemulsion (NE). R848-IVM co-loaded NE was developed and characterized in vitro. Antitumor activity of R848-IVM NE was also evaluated in vitro and in vivo. R848-IVM NE exhibited long-term stability and reduced cytotoxicity by IVM. In vivo studies demonstrated that IVM significantly augments the ICD by upregulating Cd8a and releasing HMGB1 in tumor tissue, which could enhance R848-driven antitumor immunity. R848-IVM NE treatment showed strong antitumor activity with over 80% tumor growth inhibition, suggesting a potential combination therapy of systemic co-delivering IVM with TLR agonists against solid cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, we designed a novel nucleus-targeted nanocarrier (NLS-KALA-SA, NKSN) consisting of Kala peptide (KALA), nuclear localization signal (NLS) and stearic acid (SA) using Fmoc solid phase synthesis method. We chose Curcumin (CUR), Paclitaxel (PTX), Ginsenoside compound K(CK) as models of poorly water-soluble antitumor drugs, The drugs loaded NLS-KALA-SA nanoparticles (CUR/NKSN, PTX/NKSN, CK/NKSN) were obained by the dialysis method, their physicochemical properties were determined and antitumor activity were evaluated. The NLS-KALA-SA nanoparticles were spherical shaped with an average size of 76.4 ± 7.6 mm and a zeta potential of 43.7 ± 5.8 mV. The drug-loaded NLS-KALA-SA nanoparticles were above 86.1% and 17.1% in entrapment efficiency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that PTX/NKSN mainly distributed in tumor site of A549-bearing mice, and coumarin-6(C6) loaded NLS-KALA-SA nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of A549 cells. Western blot analysis indicated that PTX/NKSN could more remarkably inhibit Bcl-2 expression and enhance the expression of Bax and Caspase-3 as compared to the controls in A549 cells. Cell apoptosis and antitumor activity study showed that PXT/NKSN could more obviously induce apoptosis of A549 cells compared with free PXT, the PTX/NKSN administration was more effective than free PTX for lung cancer treatment and displayed mild toxicity in A549-bearing mice. The results demonstrates that the NLS-KALA-SA nanoparticles system could enhance the antitumor effects of the encapsulated drug and reduce tissue toxicity due to its long circulating properties and tumor targeting, which might provide a promising strategy for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Drug release from liposomes in the endosome-lysosomal organelles into cytoplasm is critical to cytotoxicity and anticancer effects. Chloroquine is a lysosomotropic agent that has been reported to enhance in vitro cytotoxicity of basic anticancer drugs. To investigate the mechanism of chloroquine triggering basic anticancer drugs release from liposomes and the potential to treat solid tumors in clinic, daunorubicin was loaded into folate-targeted liposomes by ammonium sulfate remote loading method. In vitro triggered release profiles showed that chloroquine can instantly expel about 11% daunorubicin out of liposomes. In vitro cytotoxicity of folate-targeted liposomal daunorubicin on L1210JF(FR+) was enhanced by chloroquine, which was further confirmed by confocal micrographs. Intraliposomal pH was increased by adding chloroquine into 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) liposomes with ammonium sulfate gradient, but was not higher than 5.5. Ion exchange and pH rising are the most plausible mechanisms of chloroquine triggering daunorubicin release from liposomes. In vivo anticancer effects on a murine solid tumor model with L1210JF indicated that chloroquine induced daunorubicin release from liposomes as well. Overall, these results support the potential application of chloroquine to trigger the release of liposomal drugs and ultimately to improve the therapeutic efficacy. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:5011-5018, 2010 [ABSTRACT FROM AUTHOR]

Fludarabine (FLU)-based combination therapies are commonly used to treat low-grade lymphoma and chronic lymphocytic leukemia (CLL) patients. In vitro and clinical studies have indicated advantages when FLU and mitoxantrone (MTO) are applied in combination. To further enhance this effect, these two agents were coencapsulated in liposomes. FLU was passively encapsulated during liposome formation, and MTO was loaded with a transmembrane pH gradient. Entrapment efficiency, particle size, stability, and drug release kinetics were characterized. In vitro cytotoxicity study was carried out in two representative B-cell lines: Wac3CD5 and Raji. Synergism as measured by combination index (CI) was observed in cells treated with liposomes coencapsulating FLU and MTO. Annexin V/propidium iodide (PI) analysis further confirmed that coencapsulated FLU and MTO improved the percentage of apoptosis among primary CLL cells. These data suggest that adopting liposomes containing coencapsulated drug combinations constitutes a potential strategy to promote drug synergism and may have utility in the treatment of leukemia and lymphoma. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1508–1518, 2008 [ABSTRACT FROM AUTHOR]

Phospholipids have been extensively evaluated as an anchor for both PEGylation and receptor-targeting in liposomal formulations. However, cholesterol, another important component in biomembranes, has not been fully investigated as an alternative anchor. In this study, the potential role of cholesterol for anchoring PEG and folate was investigated. Cholesterol derivatives were synthesized for PEGylation (mPEG-cholesterol) and folate receptor (FR) targeting (folate-PEG-cholesterol) and incorporated into the bilayer of FR-targeted liposomal doxorubicin. The colloidal stability of these cholesterol derivative-containing liposomes was superior to non-PEGylated liposomes, indicating that steric barrier provided by mPEG-cholesterol can efficiently inhibit aggregation of liposomes. FR-targeting activity of these liposomes was demonstrated by in vitro cell-binding studies on FR-overexpressing KB cells. In addition, in vivo circulation of cholesterol-anchored liposomes was prolonged compared to non-PEGylated liposomes. These studies suggest that cholesterol is a viable bilayer anchor for synthesis of PEGylated and FR-targeted liposomes. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2424–2435, 2007 [ABSTRACT FROM AUTHOR]

A correction to the article "Cholesterol as a bilayer anchor for PEGylation and targeting ligand in folate-receptor-targeted liposomes," by Xiaobin B. Zhao and colleagues in the 2007 issue is presented.