Matrix Metalloproteinase- and pH-Sensitive Nanoparticle System Enhances Drug Retention and Penetration in Glioblastoma.

Glioblastoma (GBM) is a primary malignant brain tumor with limited therapeutic options. One promising approach is local drug delivery, but the efficacy is hindered by limited diffusion and retention. To address this, we synthesized and developed a dual-sensitive nanoparticle (Dual-NP) system, formed between a dendrimer and dextran NPs, bound by a dual-sensitive [matrix metalloproteinase (MMP) and pH] linker designed to disassemble rapidly in the tumor microenvironment. The disassembly prompts the in situ formation of nanogels via a Schiff base reaction, prolonging Dual-NP retention and releasing small doxorubicin (Dox)-conjugated dendrimer NPs over time. The Dual-NPs were able to penetrate deep into 3D spheroid models and detected at the tumor site up to 6 days after a single intratumoral injection in an orthotopic mouse model of GBM. The prolonged presence of Dual-NPs in the tumor tissue resulted in a significant delay in tumor growth and an overall increase in survival compared to untreated or Dox-conjugated dendrimer NPs alone. This Dual-NP system has the potential to deliver a range of therapeutics for efficiently treating GBM and other solid tumors.

Polymeric microneedles enable simultaneous delivery of cancer immunomodulatory drugs and detection of skin biomarkers.

Background: Immune-modulating therapies impart positive outcomes in a subpopulation of cancer patients. Improved delivery strategies and non-invasive monitoring of anti-tumor effects can help enhance those outcomes and understand the mechanisms associated with the generation of anti-tumor immune responses following immunotherapy. Methods: We report on the design of a microneedle (MN) platform capable of simultaneous delivery of immune activators and collection of interstitial skin fluid (ISF) to monitor therapeutic responses. While either approach has shown promise, the integration of the therapy and diagnostic arms into one MN platform has hardly been explored before. MNs were synthesized out of crosslinked hyaluronic acid (HA) and loaded with a model immunomodulatory nanoparticle-containing drug, CpG oligodinucleotides (TLR9 agonist), for cancer therapy in melanoma and colon cancer models. The therapeutic response was monitored by longitudinal analysis of entrapped immune cells in the MNs following patch retrieval and digestion. Results: Transdermal delivery of CpG-containing NPs with MNs induced anti-tumor immune responses in multiple syngeneic mouse cancer models. CpG-loaded MNs stimulated innate immune cells and reduced tumor growth. Intravital microscopy showed deposition and spatiotemporal co-localization of CpG-NPs within the tumor microenvironment when delivered with MNs. Analysis of MN-sampled ISF revealed similar immune signatures to those seen in the bulk tumor homogenate, such as increased populations of macrophages and effector T cells following treatment. Conclusions: Our hydrogel-based MNs enable effective transdermal drug delivery into immune cells in the tumor microenvironment, and upon retrieval, enable studying the immune response to the therapy over time. This platform has the theranostic potential to deliver a range of combination therapies while detecting biomarkers.

Investigation of the enhanced antitumour potency of STING agonist after conjugation to polymer nanoparticles.

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(ß-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells-rather than cancer cells-and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy.

Immunology-Guided Biomaterial Design for Mucosal Cancer Vaccines.

Cancer of mucosal tissues is a major cause of worldwide mortality for which only palliative treatments are available for patients with late-stage disease. Engineered cancer vaccines offer a promising approach for inducing antitumor immunity. The route of vaccination plays a major role in dictating the migratory pattern of lymphocytes, and thus vaccine efficacy in mucosal tissues. Parenteral immunization, specifically subcutaneous and intramuscular, is the most common vaccination route. However, this induces marginal mucosal protection in the absence of tissue-specific imprinting signals. To circumvent this, the mucosal route can be utilized, however degradative mucosal barriers must be overcome. Hence, vaccine administration route and selection of materials able to surmount transport barriers are important considerations in mucosal cancer vaccine design. Here, an overview of mucosal immunity in the context of cancer and mucosal cancer clinical trials is provided. Key considerations are described regarding the design of biomaterial-based vaccines that will afford antitumor immune protection at mucosal surfaces, despite limited knowledge surrounding mucosal vaccination, particularly aided by biomaterials and mechanistic immune-material interactions. Finally, an outlook is given of how future biomaterial-based mucosal cancer vaccines will be shaped by new discoveries in mucosal vaccinology, tumor immunology, immuno-therapeutic screens, and material-immune system interplay.

Nanotechnology in the diagnosis and treatment of lung cancer.

Lung cancer is an umbrella term for a subset of heterogeneous diseases that are collectively responsible for the most cancer-related deaths worldwide. Despite the tremendous progress made in understanding lung tumour biology, advances in early diagnosis, multimodal therapy and deciphering molecular mechanisms of drug resistance, overall curative outcomes remain low, especially in metastatic disease. Nanotechnology, in particular nanoparticles (NPs), continue to progressively impact the way by which tumours are diagnosed and treated. The unique physicochemical properties of materials at the nanoscale grant access to a diverse molecular toolkit that can be manipulated for use in respiratory oncology. This realisation has resulted in several clinically approved NP formulations and many more in clinical trials. However, NPs are not a panacea and have yet to be utilised to maximal effect in lung cancer, and medicine in a wider context. This review serves to: describe the complexity of lung cancer, the current diagnostic and therapeutic environment, and highlight the recent advancements of nanotechnology based approaches in diagnosis and treatment of respiratory malignancies. Finally, a brief outlook on the future directions of nanomedicine is provided; presently the full potential of the field is yet to be realised. By gleaning lessons and integrating advancements from neighbouring disciplines, nanomedicine can be elevated to a position where the current barriers that stymie full clinical impact are lifted.

Tyrosine Kinase Inhibitor Gold Nanoconjugates for the Treatment of Non-Small Cell Lung Cancer.

Gold nanoparticles (AuNPs) have emerged as promising drug delivery candidates that can be leveraged for cancer therapy. Lung cancer (LC) is a heterogeneous disease that imposes a significant burden on society, with an unmet need for new therapies. Chemotherapeutic drugs such as afatinib (Afb), which is clinically approved for the treatment of epidermal growth factor receptor positive LC, is hydrophobic and has low bioavailability leading to spread around the body, causing severe side effects. Herein, we present a novel afatinib-AuNP formulation termed Afb-AuNPs, with the aim of improving drug efficacy and biocompatibility. This was achieved by synthesis of an alkyne-bearing Afb derivative and reaction with azide-functionalized lipoic acid using copper-catalyzed click chemistry, then conjugation to AuNPs via alkylthiol-gold bond formation. The Afb-AuNPs were found to possess up to 3.7-fold increased potency when administered to LC cells in vitro and were capable of significantly inhibiting cancer cell proliferation, as assessed by MTT assay and electric cell-substrate impedance sensing, respectively. Furthermore, when exposed to Afb-AuNPs, human alveolar epithelial type I-like cells, a model of the healthy lung epithelium, maintained viability and were found to release less proinflammatory cytokines when compared to free drug, demonstrating the biocompatibility of our formulation. This study provides a new platform for the development of nontraditional AuNP conjugates which can be applied to other molecules of therapeutic or diagnostic utility, with potential to be combined with photothermal therapy in other cancers.