Two-Wave Nanotherapy To Target the Stroma and Optimize Gemcitabine Delivery To a Human Pancreatic Cancer Model in Mice

ArticleinACS Nano 7(11) · October 2013with35 Reads
DOI: 10.1021/nn404083m · Source: PubMed
Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access, because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-β signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The co-polymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH dependent LY364947 release from the MSNPs, we achieved rapid entry of IV injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but also introduces the concept of using a step-wise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.
    • "PDAC elicits a dense stromal response that limits vascular access due to pericyte coverage of vascular fenestrations and is a contributing factor to chemotherapy resistance. Tumor-bearing mice treated with an initial delivery of MSNPs containing the TGF-β inhibitor, LY364947, to decrease vascular pericyte coverage, followed by treatment with liposomes containing gemcitabine showed reduced tumor burden compared to treatment with free drug or gemcitabine-loaded liposomes only [236]. Thus, MSNPs show promise for delivering a wide variety of chemotherapy agents with decreased toxicity [233, 235, 238, 244, 245], and may resurrect shelved drugs such as selenocystine [189], whose clinical use has been hindered by low stability or solubility. "
    [Show abstract] [Hide abstract] ABSTRACT: Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.
    Article · Jan 2016
    • "Unconspicuous toxicity was shown in histological sections of various organs for HTSL + GNR + NIR treated group (Fig. 7). The representative characteristics of tissue damage, such as degeneration of myocardial, necrosis of hepatocytes [42] , and edema Bowman's space of kidney tis- sues [43], were not shown in microscopic images. The nanocarriers with sizes of 70–200 nm were considered to be cleared by liver and spleen, leading to high concentration and toxicity in these organs. "
    [Show abstract] [Hide abstract] ABSTRACT: The primary challenge of cancer therapeutic was the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious systemic side effects. We designed a tumor-targeting accumulated and locally triggered-release nanocarrier system to increase the intratumoral drug concentration and thus the efficacy of chemotherapy, based on gold nanorods (GNRs) and thermosensitive liposomes (TSL). PEGylated GNRs could not only made nanocarriers to co-accumulate in tumors depending on enhanced permeability and retention (EPR) effect, but also generated heat locally under near-infrared (NIR) stimulation. CO2 bubbles were generated by the encapsulated ammonium bicarbonate (ABC) under hyperthermia, thus the co-encapsulated drug was released and local drug concentration was increased along with the disintegration of liposomal membrane. On the other hand, this dual-targeting system prevented the drug leakage in blood circulation or other organs while facilitated most of active agents deliver to tumors. In vitro and in vivo experiments revealed high cytotoxicity and good affinity of HTSL to MDA-MB-435 cells when used synergistically with GNRs, but low toxicity to normal cells at the same condition. When combined with thermotherapy, the smart nanocarrier system held significant promise for future cancer treatment for their markedly improved therapeutic efficacy and decreased systemic toxicity. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015
    • "A high resistance to chemotherapy and prominent desmoplastic stroma are two main contributing factors to the poor outcome of pancreatic cancer. Our group and others have increasingly recognized the critical role of tumor stroma in pancreatic cancer chemoresistance [11, 23, 24]. PSCs are a critical cellular component of pancreatic cancer stroma. "
    [Show abstract] [Hide abstract] ABSTRACT: Pancreatic cancer exhibits the poorest prognosis among all tumors and is characterized by high resistance to the currently available chemotherapeutic agents. Our previous studies have suggested that stromal components could promote the chemoresistance of pancreatic cancer cells (PCCs). Here, we explored the roles of pancreatic stellate cells (PSCs) and the SDF-1α/CXCR4 axis in pancreatic cancer chemoresitance. Our results showed that primary PSCs typically expressed SDF-1α, whereas its receptor CXCR4 was highly expressed in PCCs. PSC-conditioned medium (PSC-CM) inhibited Gemcitabine (GEM)-induced cytotoxicity and apoptosis in the human PCC line Panc-1, which was antagonized by an SDF-1α neutralizing Ab. Recombinant human SDF-1α (rhSDF-1α) increased IL-6 expression and secretion in Panc-1 cells in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. rhSDF-1α protected Panc-1 cells from GEM-induced apoptosis, and the protective effect was significantly reduced by blocking IL-6 using a neutralizing antibody. Moreover, rhSDF-1α increased FAK, ERK1/2, AKT and P38 phosphorylation in Panc-1 cells, and either FAK or ERK1/2 inhibition suppressed SDF-1α-upregulated IL-6 expression. SDF-1α-induced AKT activation was almost completely blocked by FAK inhibition. In conclusion, we demonstrate for the first time that PSCs promote the chemoresistance of PCCs to GEM, and this effect is mediated by paracrine SDF-1α/CXCR4 signaling-induced activation of the intracellular FAK-AKT and ERK1/2 signaling pathways and a subsequent IL-6 autocrine loop in PCCs. Our findings indicate that blocking the PSC-PCC interaction by inhibiting SDF-1α/CXCR4 signaling may be a promising therapeutic strategy for overcoming chemoresistance in pancreatic cancer.
    Full-text · Article · Dec 2014
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