Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity.

Background Aims: Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy.

Methods: MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry.

Locoregional delivery of CAR-T cells in the clinic.

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment.

Cyto-Immuno-Therapy for Cancer: A Pathway Elicited by Tumor-Targeted, Cytotoxic Drug-Packaged Bacterially Derived Nanocells.

Immunotherapy has emerged as a powerful new chapter in the fight against cancer. However, it has yet to reach its full potential due in part to the complexity of the cancer immune response. We demonstrate that tumor-targeting EDV nanocells function as an immunotherapeutic by delivering a cytotoxin in conjunction with activation of the immune system.

Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery.

Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70%; however, children are often left with long-term treatment side effects. New therapies that maintain a high cure rate while reducing off-target toxicity are required.

Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma.

Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDV) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell.

Choice of Capping Group in Tripeptide Hydrogels Influences Viability in the Three-Dimensional Cell Culture of Tumor Spheroids.

Two peptide-derived low-molecular-weight gelators bearing different capping groups, 9-fluorenylmethyloxycarbonyl (Fmoc) and phenothiazine, were synthesized and their gel networks were characterized. The variation of the N-terminal capping group affects the viability of these hydrogels as a three-dimensional cell culture for multicellular tumor spheroids. These results indicate that the phenothiazine capping group is a more biocompatible alternative to the widely used Fmoc moiety.

A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo.

Pancreatic cancer is a devastating disease with a dismal prognosis. Short-interfering RNA (siRNA)-based therapeutics hold promise for the treatment of cancer. However, development of efficient and safe delivery vehicles for siRNA remains a challenge.

The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers.

Previously synthesized poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA) copolymers were examined as potential drug delivery vehicles. P(MAA-co-CMA) copolymers were fluorescently labelled and imaged in SHEP and HepG2 cells. To understand their cell internalization pathway endocytic inhibition studies were conducted.

Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide due its resistance to chemotherapy and aggressive tumor growth. Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in cancer cells, and plays a major role in regulating tumor growth. A number of PLK1 inhibitors are in clinical trial; however, poor tumor bioavailability and off-target effects limit their efficacy.

TUBB3/βIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer.

βIII-tubulin (encoded by TUBB3) expression is associated with therapeutic resistance and aggressive disease in non-small cell lung cancer (NSCLC), but the basis for its pathogenic influence is not understood. Functional and differential proteomics revealed that βIII-tubulin regulates expression of proteins associated with malignant growth and metastases. In particular, the adhesion-associated tumor suppressor maspin was differentially regulated by βIII-tubulin.

Drug delivery: beyond active tumour targeting.

Unlabelled: Despite improvements in our understanding of cancer and the concept of personalised medicine, cancer is still a major cause of death. It is established that solid tumours are highly heterogeneous, with a complex tumour microenvironment. Indeed, the tumour microenvironment is made up of a collection of immune cells, cancer-activated fibroblasts, and endothelial cells and in some cases a dense extracellular matrix.

Stimuli-responsive functionalized mesoporous silica nanoparticles for drug release in response to various biological stimuli.

A silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system has been synthesized and characterized. The system uses l-cysteine derivatized gold nanoparticles (AuNPs), bound to the MSNs using Cu as a bridging ion. The AuNPs serve as removable caps that hinder the release of drug molecules inside the amino functionalized MSN mesoporous framework.

Dextran-based doxorubicin nanocarriers with improved tumor penetration.

Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of ∼300 nM against two-dimensional (2D) SK-N-BE(2) monolayers.

Assessment of cholesterol-derived ionic copolymers as potential vectors for gene delivery.

A library of cholesterol-derived ionic copolymers were previously synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization as 'smart' gene delivery vehicles that hold diverse surface charges. Polyplex systems formed with anionic poly(methacrylic acid-co-cholesteryl methacrylate) (P(MAA-co-CMA)) and cationic poly(dimethylamino ethyl methacrylate-co-cholesteryl methacrylate) (Q-P(DMAEMA-co-CMA)) copolymer series were evaluated for their therapeutic efficiency. Cell viability assays, conducted on SHEP, HepG2, H460, and MRC5 cell lines, revealed that alterations in the copolymer composition (CMA mol %) affected the cytotoxicity profile.

Effective delivery of siRNA into cancer cells and tumors using well-defined biodegradable cationic star polymers.

Cancer is one of the most common causes of death worldwide. Two types of cancer that have high mortality rates are pancreatic and lung cancer. Despite improvements in treatment strategies, resistance to chemotherapy and the presence of metastases are common.

Functionalizing biodegradable dextran scaffolds using living radical polymerization: new versatile nanoparticles for the delivery of therapeutic molecules.

Conferring biodegradability to nanoparticles is vitally important when nanomedicine applications are being targeted, as this prevents potential problems with bioaccumulation of byproducts after delivery. In this work, dextran has been modified (and rendered hydrophobic) by partial acetalation. A solid state NMR method was first developed to fully characterize the acetalated polymers.

Nonionic diethanolamide amphiphiles with saturated hydrocarbon chains: neat crystalline and lyotropic liquid crystalline phase behavior.

The solid state and lyotropic phase behavior of a series of nonionic diethanolamide amphiphiles with increasing saturated hydrocarbon chain length (lauroyl, myristoyl, palmitoyl, and stearoyl) has been examined. All four saturated diethanolamide amphiphiles form a crystalline solid with two or three different polymorphic crystalline forms at room temperature. Melting points and associated enthalpies for these four amphiphiles increased with increasing chain length.

Nonionic diethanolamide amphiphiles with isoprenoid-type hydrocarbon chains: thermotropic and lyotropic liquid crystalline phase behaviour.

The thermotropic and lyotropic liquid crystalline phase behaviour of a series of diethanolamide amphiphiles with isoprenoid-type hydrocarbon chains (geranoyl, H-farnesoyl, and phytanoyl) has been investigated. When neat, both H-farnesoyl and phytanoyl diethanolamide form a smectic liquid crystalline structure at sub-zero temperatures. In addition, all three diethanolamides exhibit a glass transition temperature at around -73 °C.

Nonionic diethanolamide amphiphiles with unsaturated C18 hydrocarbon chains: thermotropic and lyotropic liquid crystalline phase behavior.

The neat and lyotropic liquid crystalline phase behavior of three nonionic diethanolamide amphiphiles with C18 hydrocarbon chains containing one, two or three unsaturated bonds has been examined. This has allowed the effect of degree of unsaturation on the phase behavior of diethanolamide amphiphiles to be investigated. Neat linoleoyl and linolenoyl diethanolamide undergo a transition from a glassy liquid crystal to a liquid crystal at ∼-85 °C, while neat oleoyl diethanolamide undergoes a transition at ∼-60 °C to a liquid crystalline material before re-crystallizing at -34 °C.

Lamellar crystalline self-assembly behaviour and solid lipid nanoparticles of a palmityl prodrug analogue of Capecitabine--a chemotherapy agent.

An amphiphile prodrug, 5'-deoxy-5-fluoro-N(4)-(palmityloxycarbonyl) cytidine or 5'-deoxy-5-fluoro-N(4)-(hexadecanaloxycarbonyl) cytidine (5-FCPal), consisting of the same head group as the commercially available chemotherapeutic agent Capecitabine, linked to a palmityl hydrocarbon chain via a carbamate bond is reported. Thermal analysis of this prodrug indicates that it melts at ∼115 °C followed quickly by degradation beginning at ∼120 °C. The neat solid 5-FCPal amphiphile acquires a lamellar crystalline arrangement with a d-spacing of 28.

Lyotropic liquid crystalline self-assembly material behavior and nanoparticulate dispersions of a phytanyl pro-drug analogue of capecitabine-a chemotherapy agent.

An amphiphile prodrug, 5'-deoxy-5-fluoro-N⁴-(phytanyloxycarbonyl) cytidine (5-FCPhy) has been prepared and investigated for its self-assembly material properties, in vitro cytotoxicity, and in vivo efficacy as a chemotherapy agent. The phase transitions and stability of the neat amphiphile were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). X-ray diffraction (XRD) was used to confirm the structure of the neat amphiphile, which was an amorphous glassy material.

Monodisperse nonionic isoprenoid-type hexahydrofarnesyl ethylene oxide surfactants: high throughput lyotropic liquid crystalline phase determination.

The neat and lyotropic phase behavior of eight new ethylene oxide amphiphiles (EO = 1-8) with a hexahydrofarnesyl chain (3,7,11-trimethyldodecyl) and narrow polydispersity (>98.5% purity) is reported. Below five EO units the behavior of the neat surfactants show only a glass transition, Tg ∼ -90 °C.

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents.

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site.