Context Celastrol, a natural compound derived from the herb Tripterygium wilfordii, is known to have anticancer activity, but is not soluble in water. Objective Formation of celastrol liposomes, to avoid the use of toxic solubilizing agents. Materials and methods Two different formulations of pegylated celastrol liposomes were fabricated. Liposomal characteristics and serum stability were determined using dynamic light scattering. Drug entrapment efficacy and drug release were measured spectrophotometrically. Cellular internalization and anticancer activity was measured in prostate cancer cells. Results Liposomal celastrol displayed efficient serum stability, cellular internalization and anticancer activity, comparable to that of the free drug reconstituted in dimethyl sulfoxide. Discussion and conclusion Liposomal celastrol can decrease the viability of prostate cancer cells, while eliminating the need for toxic solubilizing agents.

Hesperetin is a compound from citrus fruit that has previously been found to exert anticancer activity through a variety of mechanisms. However, the application of hesperetin to cancer therapy has been hampered by its hydrophobicity, necessitating the use of toxic solubilizing agents. Here, we have developed the first liposome-based delivery system for hesperetin. Liposomes were fabricated using the thin-layer evaporation technique and physical and pharmacological parameters were measured. The liposomes remained stable for prolonged periods of time in serum and under storage conditions, and displayed anticancer efficacy in both H441 lung cancer cells and MDA-MB-231 breast cancer cells. Furthermore, the anticancer activity was not impaired in cells expressing the multidrug resistance protein 1 (MDR-1). In conclusion, the encapsulation of hesperetin in liposomes does not interfere with therapeutic efficacy and provides a biocompatible alternative to toxic solubilizing agents, thereby enabling future clinical use of this compound for cancer therapy.

The mechanism for improved therapeutic efficacy of the combination therapy with albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of: (1)encapsulating nAb-PTX in multistage nanovectors (MSV); (2)effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX+gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX+gem also caused a substantial increase in tumor PTX accumulation and significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by: (1)gem through up-regulation of caveolin-1; (2)MSV through increasing accumulation of nAb-PTX in the tumor.

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The purpose of this study was to evaluate the effect of encapsulation of albumin-bound paclitaxel (ABX) in multistage nanovector (MSV) administered in combination with gemcitabine (Gem) in pancreatic ductal adenocarcinoma (PDA) therapy. PDA is one of the most aggressive malignancies with a 5-year survival rate of less than 3%. The inefficiency in treatment of primary pancreatic cancer can be related to the biophysical barriers in the tumor microenvironment which prevent delivery of therapeutics to the lesion. The best chemotherapy currently available for PDA is the combination therapy with Gem + ABX, which was reported to extend the overall survival as compared to patients receiving Gem alone by <2 months. ABX utilizes endogenous albumin pathways of endothelial transcytosis (gp60) and intratumoral binding of SPARC to transport the drug into the tumor's interstitium. Our previous studies in several tumor models report that MSV can overcome biophysical barriers and carry therapeutic cargo to the tumor microenvironment increasing therapeutic efficacy of the drug. In this study, we used ABX loaded into the MSV in combination with Gem to improve the therapeutic efficacy of the ABX + Gem combination in PDA. We further evaluated transport mechanisms which can be responsible for the observed efficacy. Mice bearing orthotopic PDA tumors (L3.6pl) were treated once a week for up to four months with ABX, Gem, ABX + Gem, MSV/ABX, MSV or MSV/ABX + Gem and PBS control. Subsets of mice were sacrificed after the first and third treatment. Levels of the drugs in tumor/plasma were evaluated by LC/MS-MS. Tumors were immunostained for evaluation of apoptosis (TUNEL), proliferation (Ki67) and the tumor stromal components (F4/80, CD204, CD31, SPARC). Survival of remaining animals was monitored (n = 10/group). The results indicate that treatment with MSV/ABX + Gem was highly efficient prolonging the survival of 50% of the animals until sacrificed at the endpoint of the study at four months as compared to median survival of ABX + Gem mice of 70.5 days. MSV/ABX + Gem increased tumor levels of paclitaxel in comparison to treatment with Gem + ABX. Furthermore, the use of the MSV system as a delivery vehicle resulted in increased macrophage infiltration and SPARC expression in the tumor, while reducing cancer cell proliferation and increasing apoptosis. In conclusion, MSV/ABX + Gem outperforms the current standard-of-care (ABX + Gem) in a mouse model of PDA. The possible mechanism is related to increased transport of ABX encapsulated in MSV/ABX mediated by macrophages or SPARC. Citation Format: Carlotta Borsoi, Kenji Yokoi, Fransisca Leonard, Mauro Ferrari, Biana Godin Vilentchouk. Enhanced therapeutic efficacy of a combination of gemcitabine and albumin-bound paclitaxel in multistage nanovectors in pancreatic ductal adenocarcinoma: Evaluation of transport phenomena. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2015-2833