Development of Facile and Versatile Platinum Drug Delivering Silicasome Nanocarriers for Efficient Pancreatic Cancer Chemo-Immunotherapy.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC8035264 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is an urgent need to develop new life-prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo-immunotherapy response in an orthotopic Kras-dependent pancreatic cancer model. This discovery is premised on the weak-basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death-ligand 1 (PD-L1) expression. ICD is characterized by calreticulin expression and high-mobility group box 1 (HMGB1) release in dying Kras-induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti-PD-1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD-L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo-immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti-PD-1 leads to significantly enhanced survival improvement, and is far superior to anti-PD-1 plus either free irinotecan or Onivyde.
| S-EPMC7967046 | biostudies-literature
Project description:Nanomedicine has stepped into the spotlight of radiation therapy over the last two decades. Nanoparticles (NPs), especially metallic NPs, can potentiate radiotherapy by specific accumulation into tumors, thus enhancing the efficacy while alleviating the toxicity of radiotherapy. Water radiolysis is a simple, fast and environmentally-friendly method to prepare highly controllable metallic nanoparticles in large scale. In this study, we used this method to prepare biocompatible PEGylated (with Poly(Ethylene Glycol) diamine) platinum nanoflowers (Pt NFs). These nanoagents provide unique surface chemistry, which allows functionalization with various molecules such as fluorescent markers, drugs or radionuclides. The Pt NFs were produced with a controlled aggregation of small Pt subunits through a combination of grafted polymers and radiation-induced polymer cross-linking. Confocal microscopy and fluorescence lifetime imaging microscopy revealed that Pt NFs were localized in the cytoplasm of cervical cancer cells (HeLa) but not in the nucleus. Clonogenic assays revealed that Pt NFs amplify the gamma rays induced killing of HeLa cells with a sensitizing enhancement ratio (SER) of 23%, thus making them promising candidates for future cancer radiation therapy. Furthermore, the efficiency of Pt NFs to induce nanoscopic biomolecular damage by interacting with gamma rays, was evaluated using plasmids as molecular probe. These findings show that the Pt NFs are efficient nano-radio-enhancers. Finally, these NFs could be used to improve not only the performances of radiation therapy treatments but also drug delivery and/or diagnosis when functionalized with various molecules.
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Project description:Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC) cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a liposome) was introduced to provide encapsulated irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace irinotecan in FOLFIRINOX, the liposomal formulation is currently prescribed as a second-line treatment option (in combination with 5-fluorouracil and leucovorin) for patients with metastatic PDAC who failed gemcitabine therapy. However, the toxicity of Onivyde remains a concern that needs to be addressed for use in CRC as well. Our goal was to custom design a mesoporous silica nanoparticle (MSNP) carrier for encapsulated irinotecan delivery in a robust CRC model. This was achieved by developing an orthotopic tumor chunk model in immunocompetent mice. With a view to increase the production volume and to expand the disease applications, the carrier design was improved by using an ethanol exchange method for coating of a supported lipid bilayer (LB) that entraps a protonating agent. The encapsulated protonating agent was subsequently used for remote loading of irinotecan. The excellent irinotecan loading capacity and stability of the LB-coated MSNP carrier, also known as a "silicasome", previously showed improved efficacy and reduced toxicity when compared to an in-house liposomal carrier in a PDAC model. Intravenous injection of the silicasomes in a well-developed orthotopic colon cancer model in mice demonstrated improved pharmacokinetics and tumor drug content over free drug and Onivyde. Moreover, improved drug delivery was accompanied by substantially improved efficacy, increased survival, and reduced bone marrow and GI toxicity compared to the free drug and Onivyde. We also confirmed that the custom-designed irinotecan silicasomes outperform Onivyde in an orthotopic PDAC model. In summary, the Ir-silicasome appears to be promising as a treatment option for CRC in humans based on improved efficacy and the carrier's favorable safety profile.
| S-EPMC6554030 | biostudies-literature
Project description:Checkpoint blocking antibodies that interfere in the PD-1/PD-L1 axis provide effective cancer immunotherapy for tumors that are immune inflamed or induced to become "hot". It has also been demonstrated that a small molecule inhibitor of the signaling hub kinase GSK3 can interfere in the PD-1/PD-L1 axis in T-cells by suppressing PD-1 expression. This provides an alternative approach to intervening in the PD-1/PD-L1 axis to provide cancer immunotherapy. In this communication, we demonstrate the remote loading of GSK3 inhibitor AZD1080 into the porous interior of mesoporous silica nanoparticles coated with a lipid bilayer (a.k.a. silicasomes). In a MC38 colon cancer model, intravenous injection (IV) of silicasome-encapsulated AZD1080 significantly improved biodistribution and drug delivery to the tumor site. The improved drug delivery was accompanied by cytotoxic MC38 tumor cell killing by perforin-releasing CD8+ T-cells, exhibiting reduced PD-1 expression. IV injection of encapsulated AZD1080 also resulted in significant tumor shrinkage in other syngeneic mouse tumor models, including another colorectal tumor (CT26), as well as pancreas (KPC) and lung (LLC) cancer models. Not only was the therapeutic efficacy of encapsulated AZD1080 similar or better than anti-PD-1 antibody, but the treatment was devoid of treatment toxicity. These results provide proof-of-principal demonstration of the feasibility of using encapsulated delivery of a GSK3 inhibitor to provide cancer immunotherapy, with the possibility to be used as a monotherapy or in combination with chemotherapy or other immunomodulatory agents.
| S-EPMC7870571 | biostudies-literature
Project description:Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed. Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation. Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity. Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.
| S-EPMC8825592 | biostudies-literature
Project description:Infectious diseases caused by intracellular microorganisms represent a significant challenge in medical care due to interactions among drugs during coinfections and the development of resistance in microorganisms, limiting existing therapies. This work reports on itraconazole (ITZ) encapsulated into functional polymeric nanoparticles for their targeted and controlled release into macrophages to fight intracellular infections. NPs are based on poly (lactic acid-co-glycolic acid) (PLGA) polymers of different compositions, molecular weights, and lactic acid-to-glycolic acid ratios. They were self-assembled using the high-energy nanoemulsion method and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and differential scanning calorimetry. It was studied how the polymer-to-drug ratio, changes in the aqueous phase pH, and type and concentration of surfactant affected nanocarriers' formation, drug-loading capacity, and encapsulation efficiency. Results showed that drug-loading capacity and encapsulation efficiency reached 6.7 and 80%, respectively, by lowering the pH to 5.0 and using a mixture of surfactants. Optimized formulation showed an initial immediate ITZ release, followed by a prolonged release phase that fitted better with a Fickian diffusion kinetic model and high stability at 4 and 37°C. NPs functionalized by using the adsorption and carbodiimide methods had different efficiencies, the carbodiimide approach being more efficient, stable, and reproducible. Furthermore, linking F4/80 and mannose to the NPs was demonstrated to increase J774A.1 macrophages' uptake. Overall, in vitro assays showed the nanosystem's efficacy to eliminate the Histoplasma capsulatum fungus and pave the way to design highly efficient nanocarriers for drug delivery against intracellular infections.
| S-EPMC8274696 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1-mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer-coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome-based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.
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Project description:Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44+/CD133+/Nestin+-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres ("GROW"-state) while NF-κB-RELAhigh GSCs were migrating out of the sphere ("GO"-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.
| S-EPMC9659205 | biostudies-literature
Project description:BackgroundThe majority of lung cancers are adenocarcinomas, with the proportion being 40%. The patients are mostly diagnosed in the middle and late stages with metastasis and easy recurrence, which poses great challenge to the treatment and prognosis. Platinum-based chemotherapy is a primary treatment for adenocarcinoma, which frequently causes drug resistance. As a result, it is important to uncover the mechanisms of the chemoresponse of adenocarcinoma to platinum-based chemotherapy.MethodsThe genes from the dataset GSE7880 were gathered into gene modules with the assistance of weighted gene coexpression network analysis (WGCNA), the gene trait significance absolute value (|GS|), and gene module memberships (MM). The genes from hub gene modules were calculated with a protein-protein interaction (PPI) network analysis in order to obtain a screening map of hub genes. The hub genes with both a high |GS| and MM and a high degree were selected. Furthermore, genes in the hub gene modules also went through a Gene Ontology (GO) functional enrichment analysis.Results11 hub genes in four hub gene modules (LY86, ACTR2, CDK2, CKAP4, KPNB1, RBBP4, SMAD4, MYL6, RPS27, TSPAN2, and VAMP2) were chosen as the significant hub genes. Through the GO function enrichment analysis, it was indicated that four modules were abundant in immune system functions (floralwhite), amino acid biosynthetic process (lightpink4), cell chemotaxis (navajowhite2), and targeting protein (paleturquoise). Four hub genes with the highest |GS| were verified by prognostic analysis.
| S-EPMC7811416 | biostudies-literature
Project description:Background To date, chemotherapy remains the only effective treatment of unresectable pancreatic adenocarcinoma. In the past few years, the interest in immunological anticancer therapy rises sharply. AGIG is a novel chemo-immunotherapy regimen that combines nab-paclitaxel + gemcitabine chemotherapy with sequential recombinant interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) therapy. We conducted a single-arm prospective phase II study to determine the efficacy and safety of the first-line treatment of advanced pancreatic cancer with AGIG regimen. Methods Nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) were administered intravenously to all patients on days 1 and 8 triweekly, interleukin-2 (1000000U) and GM-CSF (100 µg) were administered subcutaneously on days 3-5 after chemotherapy. The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS). Patients’ conditions along with the efficacy and safety were assessed every two cycles. Results Between 11/2018 and 01/2020, sixty-four patients were enrolled. In the sixty-four evaluable patients, the disease control rate (DCR) and overall response rate (ORR) were 76.6% and 43.75%, respectively. The median follow-up time was 12.1 (range 7.1–22.4) months. The median PFS was 5.7 (range 1.63–15.8) months. The median OS was 14.2 (range 2.9–22.0) months. The most common adverse event was fever (75%). The incidence of III/IV grade neutropenia was 4.69%. In subgroup analyses, we found that eosinophil count in the blood elevated three times higher than baseline level predicted a longer survival. Conclusions The AGIG chemo-immunotherapy regimen has presented favorable ORR, OS, and manageable toxicities as first-line therapeutic strategy of advanced pancreatic cancer treatment. This regimen may be a novel reliable therapeutic option for patients with preserved performance status. The improvement of treatment efficiency may be related to the activation of non-specific immune response. Clinical Trial Registration https://clinicaltrials.gov/. identifier NCT03768687.
| S-EPMC8548663 | biostudies-literature