Gemcitabine Combination Nano Therapies for Pancreatic Cancer.
ABSTRACT: Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy.
Project description:Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(d,l-lactic-co-glycolic acid) (PLGA) cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP) over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEMin/OPout or OPin/GEMout implantable double-layered PLGA cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered PLGA cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15 days.
Project description:Obstructive biological barriers limit the transport and efficacy of cancer nanotherapeutics. Creative manipulation of tumor microenvironment provides promising avenues towards improving chemotherapeutic response. Such strategies include the use of mechanical stimuli to overcome barriers, and increase drug delivery and therapeutic efficacy. The rational use of gold nanorod-mediated mild hyperthermia treatment (MHT) alters tumor transport properties, increases liposomal gemcitabine (Gem Lip) delivery, and antitumor efficacy in pancreatic cancer CAPAN-1 tumor model. MHT treatment leads to a threefold increase in accumulation of 80-nm liposomes and enhances spatial interstitial distribution. I.v. injection of Gem Lip and MHT treatment lead to a threefold increase in intratumor gemcitabine concentration compared to chemotherapeutic infusion alone. Furthermore, combination of MHT treatment with infusion of 12 mg kg(-1) Gem Lip leads to a twofold increase in therapeutic efficacy and inhibition of CAPAN-1 tumor growth when compared to equimolar chemotherapeutic treatment alone. Enhanced therapeutic effect is confirmed by reduction in tumor size and increase in apoptotic index where MHT treatment combined with 12 mg kg(-1) Gem Lip achieves similar therapeutic efficacy as the use of 60 mg kg(-1) free gemcitabine. In conclusion, improvements in vivo efficacy are demonstrated resulting from MHT treatment that overcome transport barriers, promote delivery, improve efficacy of nanomedicines.
Project description:Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.
Project description:Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.
Project description:High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.
Project description:Pancreatic cancer is characterized by chemoresistance after several cycles of chemotherapy, which is a major issue responsible for treatment failure of pancreatic cancer. Therefore, it is necessary to explore the specific mechanism underlying chemotherapeutic resistance to overcome this issue. Here we report that miR-1266 is dramatically elevated and correlates with poor survival and chemotherapy response in pancreatic cancer patients. Upregulation of miR-1266 enhanced the chemoresistance of pancreatic cancer cells to gemcitabine (GEM) in vitro and in vivo; conversely, inhibition of miR-1266 yielded the opposite effect. Importantly, silencing of miR-1266 restored the sensitivity of pancreatic cancer cells to GEM in a dose-dependent manner in vivo. Furthermore, our results demonstrate that miR-1266 promotes resistance of pancreatic cancer cells to GEM by targeting multiple negative regulators of the STAT3 and NF-?B pathways, including SOCS3, PTPN11, ITCH, and TNIP1, leading to constitutive activation of STAT3 and NF-?B signaling. Thus, our findings clarify a novel mechanism by which miR-1266 induces chemotherapeutic resistance in pancreatic cancer, indicating that miR-1266 may be used as chemotherapeutic response indicator. Antagomir-1266 as a chemotherapeutic sensitizer, in combination with GEM, may serve as a rational regimen in the treatment of chemotherapy-resistant pancreatic cancer.
Project description:Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved with no evidence of local or systemic toxicity. In summary, we demonstrate the development of an effective LB-MSNP nanocarrier for synergistic PTX/GEM delivery in pancreatic cancer.
Project description:Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers. TAT-ODD-procaspase-3 (TOP3) is a protein prodrug that is specifically processed and activated in hypoxia-inducible factor-active cells in cancers, leading to cell death. Here, we report combination therapies in which TOP3 was combined with gemcitabine or TS-1. As monotherapy, gemcitabine and TS-1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co-treatment with TOP3 successfully overcame this limitation in vitro. Furthermore, combination therapies of TOP3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line SUIT-2. Overall, our study indicates that the combination of TOP3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer.
Project description:Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.
Project description:Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor.A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100?mg?kg(-1), q3d × 4) alone or GEM plus iRGD peptide (8??mol?kg(-1)). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC).We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens.Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.