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Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by autoreactive T cells targeting the insulin-producing beta (β) cells. Despite advances in insulin therapy, T1DM still leads to high...

Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors., Antibody mimic Selective High-Affinity Ligand-functionalized doxorubicin-encapsulated nanoparticles have been engineered for concurrent chemo-immuno-radiotherapy of hematological cancer.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

Non-Hodgkin lymphoma (NHL) is one of the most common types of hematologic malignancies. Pretargeted radioimmunotherapy (PRIT), the sequential administration of a bispecific antibody-based primary tumor-targeting component followed by a radionucleotide-labeled treatment effector, has been developed to improve the treatment efficacy and to reduce the side effects of conventional RIT. Despite the preclinical success of PRIT, clinical trials revealed that the immunogenicity of the bispecific antibody as well as the presence of competing endogenous effector molecules often compromised the treatment. One strategy to improve PRIT is to utilize bio-orthogonal ligation reactions to minimize immunogenicity and improve targeting. Herein, we report a translatable pretargeted nanoradioimmunotherapy strategy for the treatment of NHL. This pretargeting system is composed of a dibenzylcyclooctyne (DBCO)-functionalized anti-CD20 antibody (α-CD20) tumor-targeting component and an azide- and yttrium-90-((90)Y) dual-functionalized dendrimer. The physicochemical properties of both pretargeting components have been extensively studied. We demonstrated that an optimized dual-functionalized dendrimer can undergo rapid strain-promoted azide–alkyne cycloaddition with the DBCO-functionalized α-CD20 at the physiological conditions. The treatment effector in our pretargeting system can not only selectively deliver radionucleotides to the target tumor cells but also increase the complement-dependent cytotoxicity of α-CD20 and thus enhance the antitumor effects, as justified by comprehensive in vitro and in vivo studies in mouse NHL xenograft and disseminated models.

Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite its high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA–PEG NPs. Mice bearing NSCLC xenografts were administered with dual-drug loaded NPs during CRT, which showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients.

Dual pretargeting with anti-CD20 and anti–HLA-DR allows effective therapeutic delivery of a BEZ235 nanoformulation to NHL cells., Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that results from autoreactive T cells destroying insulin-producing pancreatic beta (β) cells. The development of T1DM is associated with the deficiency of co-inhibitory immune checkpoint ligands (e.g., PD-L1, CD86, and Gal-9) in β cells. Here, a new translational approach based on metabolic glycoengineering and bioorthogonal click chemistry, which bioengineers β cells with co-inhibitory immune checkpoint molecules that induce antigen-specific immunotolerance and reverse early-onset hyperglycemia is reported. To achieve this goal, a subcutaneous injectable acellular pancreatic extracellular matrix platform for localizing the bioengineered β cells while creating a pancreas-like immunogenic microenvironment, in which the autoreactive T cells can interface with the β cells, is devised.

Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of a novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80 to 85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.

Background: Activation of the innate immune system and natural killer (NK) cells has been a key effort in cancer immunotherapy research. Several NK-cell-targeted therapeutics are under clinical investigation. Current research is focused on bispecific antibodies that can bind to and target both tumor cells and NK cells. However, NK activation remains a key challenge. One approach is to simultaneously co-activate more than one NK cell stimulatory molecule, such as 4-1BB and CD16 (FcγRIII), to increase immune activation. To achieve this, we developed a new nanoparticle (NP)-based trispecific NK cell engager (nano-TriNKE) platform that can target epidermal growth factor receptor (EGFR) overexpressing tumors and promote the recruitment and activation of NK cells to eradicate these cancer cells. Moreover, the nanoengager platform allows the targeted delivery of chemotherapeutics such as epirubicin (EPI) to further improve the therapeutic efficacy. Methods: EGFR-targeted drug-free/EPI-encapsulated nano-TriNKEs were prepared by conjugating cetuximab (anti-EGFR), anti-4-BB, and anti-CD16 agonistic antibodies to PEG-PLGA NPs. Their binding specificities were evaluated in expanded murine NK cells, EGFR-overexpressed A431 (epidermoid carcinoma), MB468 (mammary gland adenocarcinoma), and HT29 (colorectal adenocarcinoma) cells in vitro. The in vitro NK cell anticancer activities in nano-TriNKE-pretreated A431, MB468, and HT29 cells were evaluated via viability assays. We also performed comprehensive in vivo efficacy studies in A431, MB468, and HT29 tumor model to investigate the anticancer activities of EGFR-targeted drug-free/EPI-encapsulated nano-TriNKEs. Further biodistribution and mechanistic studies were performed to verify the anticancer activities of nano-TriNKEs. Results: In vitro binding assay confirmed that the EGFR-targeted nano-TriNKEs bind selectively to EGFR-overexpressed cancer cells. In vitro anticancer activity studies demonstrated that effective NK cell activation can be achieved by spatiotemporal co-activation of CD16 and 4-1BB stimulatory molecules on NK cells with nanoengagers, and that the nanoengagers are more effective than free antibodies. Comprehensive in vivo efficacy studies in A431, MB468, and HT29 tumor models demonstrated that the EGFR-targeted nano-TriNKEs can augment both NK activating agents and chemotherapy as highly effective anticancer agents, providing robust chemoimmunotherapy against a broad range of EGFR-overexpressed cancers. Conclusions: Our data demonstrated that nano-TriNKEs are more effective in NK activation than free agonistic antibodies, and that the nanoengager platform provides more effective biological targeting, which is critical in NK-mediated cancer immunotherapy. Citation Format: Kin Man Au, Steven Park, Andrew Wang. Trispecific natural killer cell nanoengagers for targeted chemoimmunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1723.

Collagen IV-targeting peptide-conjugated basement membrane-targeting nanoparticles are successfully engineered to identify early-stage blood vessel injury induced by high-dose radiotherapy.

Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.

Combining molecularly targeted agents and chemotherapeutics is an emerging strategy in cancer treatment. We engineered sub-50 nm diameter diblock copolymer nanoparticles (NPs) that can sequentially release wortmannin (Wtmn, a cell signaling inhibitor) and docetaxel (Dtxl, genotoxic anticancer agent) to cancer cells. These NPs were studied in chemoradiotherapy, an important cancer treatment paradigm, in the preclinical setting. We demonstrated that Wtmn enhanced the therapeutic efficacy of Dtxl and increased the efficiency of radiotherapy (XRT) in H460 lung cancer and PC3 prostate cells in culture. Importantly, we showed that NPs containing both Wtmn and Dtxl release the drugs in a desirable sequential fashion to maximize therapeutic efficacy in comparison to administering each drug alone. An in vivo toxicity study in a murine model validated that NPs containing both Dtxl and Wtmn do not have a high toxicity profile. Lastly, we demonstrated that Dtxl/Wtmn-coencapsulated NPs are more efficient than each single-drug-loaded NPs or a combination of both single-drug-loaded NPs in chemoradiotherapy using xenograft models. Histopathological studies and correlative studies support that the improved therapeutic efficacy is through changes in signaling pathways and increased tumor cell apoptosis. Our findings suggest that our nanoparticle system led to a dynamic rewiring of cellular apoptotic pathways and thus improve the therapeutic efficiency.

The cooling system of a plastic injection mould is important as it affects the quality and productivity of the polymeric components or assemblies. Contemporary cooling channel design is confined to simple configurations of straight-drilled coolant passageway around the mould insert. Undesirable defects resulted during injection moulding, such as warpage, are inevitable. The application of rapid tool (RT) based on solid freeform fabrication (SFF) technologies with conformal cooling channel (CCC) design has provided a profound opportunity in quality improvement of polymeric components. In this study, a novel design of variable radius conformal cooling channel (VRCCC) is proposed to achieve better uniform cooling performance. Thermal-FEA and melt flow analysis are used to validate the method.

Nowadays, with the advances of Finite Element Analysis (FEA) packages, some of the engineering and design problems such as stress or thermal deformation can be successfully solved. These are convenient for better incorporating the design constraints of various tasks such as injection molded parts, or rapid prototyping and tooling. Mesh generation is the major step of finite element method for numerical computation. Common types of mesh include triangulation or tetrahedralization. During the mesh generation process, we always find difficulty in the formation of a uniform, non-conformal mesh. The undesirable mesh will adversely influence the accuracy and meshing time of the model. This paper will, thus, propose an effective approach to extend to threedimensional (3D) mesh generation by octree balancing method so as to adjust the mesh pattern. In this paper, the implementation of octree balancing will be explained and illustrated with real life example. The proposed method includes three main steps. Problematic unbalanced octants will be detected and Steiner points will be added as appropriate before the tetrahedral mesh generation. The balanced octree will form good tetrahedral meshes for further analysis. Then the balanced and unbalanced meshes will be compared for efficiency and accuracy for mesh generation.

We report the use of near-infrared (NIR) radiation to trigger the irreversible flocculation of poly(oligo(ethylene glycol) methacrylate)-stabilised polypyrrole nanoparticles in physiological buffer.

Optical coherence tomography (OCT) is a modern high resolution subsurface medical imaging technique. Herein we describe: (i) the synthesis of a thiophene-functionalized oligo(ethylene glycol) methacrylate (OEGMA)-based statistical copolymer, denoted poly(2TMOI–OEGMA); (ii) the preparation of sterically-stabilized polypyrrole (PPy) nanoparticles of approximately 60 nm diameter; (iii) the evaluation of these nanoparticles as a NIR-absorbing optical contrast agent for high-resolution OCT imaging. We show that poly(2TMOI–OEGMA)-stabilized PPy nanoparticles exhibit similar optical properties to poly(vinyl alcohol) (PVA)-stabilized PPy nanoparticles of comparable size prepared using commercially available PVA. Spectroscopic measurements and Mie calculations indicate that both types of PPy nanoparticles strongly absorb NIR radiation above 1000 nm, suggesting their potential use as OCT contrast agents. In vitro OCT studies indicate that both types of PPy nanoparticles reduce NIR backscattering within homogeneous intralipid tissue phantoms, offering almost identical contrast performance in this medium. However, PVA-stabilized PPy nanoparticles became colloidally unstable when dispersed in physiological buffer and immersed in a solid biotissue phantom and hence failed to generate a strong contrast effect. In contrast, the poly(2TMOI–OEGMA)-stabilized PPy nanoparticles remained well-dispersed and hence exhibited a strong rapid onset contrast effect within the biotissue phantom under identical physiological conditions. Ex vivo studies performed on excised chicken and porcine skin tissue demonstrated that topical administration of a low concentration of poly(2TMOI–OEGMA)-stabilized PPy nanoparticles rapidly enhances OCT image contrast in both cases, allowing key tissue features to be readily identified.

We report on a photothermal modulation detection scheme developed using a swept source-based optical coherence tomography (OCT) system centred at 1300nm. Photothermal detection is an improved technique for studying the contrast properties of exogenous contrast agents such as highly absorbing polypyrrole (PPy) nanoparticles used for OCT imaging. The swept source based OCT system has a wavelength sweep rate of 10 kHz which is used for the phase modulation detection of various concentrations of PPy nanoparticles. PPy nanoparticles have been recently reported to be a promising candidate for OCT imaging owing to their strong NIR absorption from 700–1300nm. Phase-sensitive detection of the photothermal modulation signal is achieved using a pumped 975 nm laser beam at 80Hz and 160Hz for varying concentrations of PPy nanoparticles dispersed in 2% Intralipid phantom. A phase-sensitive detection system is realised by carrying out the phase calibration using the back reflections obtained from the coverslip used with the sample. This study provides quantitative support for the use of PPy nanoparticles as a potential biocompatible contrast agent in OCT imaging.

A near-infrared (NIR) absorbing contrast agent based on polypyrrole nanoparticles is described. Quantitative optical coherence tomography studies on tissue phantoms and Mie scattering calculations indicate their potential application for early-stage cancer diagnosis.