Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects.

With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.

Decreased Lung Metastasis in Triple Negative Breast Cancer Following Locally Delivered Supratherapeutic Paclitaxel-Loaded Polyglycerol Carbonate Nanoparticle Therapy.

Breast cancer is among the most prevalent malignancies, accounting for 685,000 deaths worldwide in 2020, largely due to its high metastatic potential. Depending on the stage and tumor characteristics, treatment involves surgery, chemotherapy, targeted biologics, and/or radiation therapy. However, current treatments are insufficient for treating or preventing metastatic disease. Herein, we describe supratherapeutic paclitaxel-loaded nanoparticles (81 wt % paclitaxel) to treat the primary tumor and reduce the risk of subsequent metastatic lesions in the lungs. Primary tumor volume and lung metastasis are reduced by day 30, compared to the paclitaxel clinical standard treatment. The ultrahigh levels of paclitaxel afford an immunotherapeutic effect, increasing natural killer cell activation and decreasing NETosis in the lung, which limits the formation of metastatic lesions.

Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence after Sarcoma Resection While Avoiding Cardiotoxicity.

Surgery is the only potentially curative treatment for localized soft-tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35% to 59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft-tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, DOX-loaded meshes (DoM) increased overall survival 4-fold compared with systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, whereas mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20 days after administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft-tissue sarcoma. SIGNIFICANCE: A proof-of-principle study in animal models shows that a novel local drug delivery approach can prevent tumor recurrence as well as drug-related adverse events following surgical resection of soft-tissue sarcomas.

Ultra-high drug loading improves nanoparticle efficacy against peritoneal mesothelioma.

Peritoneal mesothelioma is an aggressive disease with a median survival of under three years, due to a lack of effective treatment options. Mesothelioma is traditionally considered a "chemoresistant" tumor; however, low intratumoral drug levels coupled with the inability to administer high systemic doses suggests that therapeutic resistance may be due to poor drug delivery rather than inherent biology. While patient survival may improve with repetitive local intraperitoneal infusions of chemotherapy throughout the perioperative period, these regimens carry associated toxicities and significant peri-operative morbidity. To circumvent these issues, we describe ultra-high drug loaded nanoparticles (NPs) composed of a unique poly(1,2-glycerol carbonate)-graft-succinate-paclitaxel (PGC-PTX + PTX) conjugate. PGC-PTX + PTX NPs are cytotoxic, localize to tumor in vivo, and improve survival in a murine model of human peritoneal mesothelioma after a single intraperitoneal (IP) injection compared to multiple weekly doses of the clinically utilized formulation PTX-C/E. Given their unique pharmacokinetics, a second intraperitoneal dose of PGC-PTX + PTX NPs one month later more than doubles the overall survival compared to the clinical control (122 versus 58 days). These results validate the clinical potential of prolonged local paclitaxel to treat intracavitary malignancies such as mesothelioma using a tailored polymer-mediated nanoparticle formulation.

An Allosteric Transcription Factor DNA-Binding Electrochemical Biosensor for Progesterone.

We describe an electrochemical strategy to transduce allosteric transcription factor (aTF) binding affinity to sense steroid hormones. Our approach utilizes square wave voltammetry to monitor changes in current output as a progesterone (PRG)-specific aTF (SRTF1) unbinds from the cognate DNA sequence in the presence of PRG. The sensor detects PRG in artificial urine samples with sufficient sensitivity suitable for clinical applications. Our results highlight the capability of using aTFs as the biorecognition elements to develop electrochemical point-of-care biosensors for the detection of small-molecule biomarkers and analytes.

Mega macromolecules as single molecule lubricants for hard and soft surfaces.

A longstanding goal in science and engineering is to mimic the size, structure, and functionality present in biology with synthetic analogs. Today, synthetic globular polymers of several million molecular weight are unknown, and, yet, these structures are expected to exhibit unanticipated properties due to their size, compactness, and low inter-chain interactions. Here we report the gram-scale synthesis of dendritic polymers, mega hyperbranched polyglycerols (mega HPGs), in million daltons. The mega HPGs are highly water soluble, soft, nanometer-scale single polymer particles that exhibit low intrinsic viscosities. Further, the mega HPGs are lubricants acting as interposed single molecule ball bearings to reduce the coefficient of friction between both hard and soft natural surfaces in a size dependent manner. We attribute this result to their globular and single particle nature together with its exceptional hydration. Collectively, these results set the stage for new opportunities in the design, synthesis, and evaluation of mega polymers.

A Synthetic Bioinspired Carbohydrate Polymer with Mucoadhesive Properties.

Mucoadhesive polymers are of significant interest to the pharmaceutical, medical device, and cosmetic industries. Polysaccharides possessing charged functional groups, such as chitosan, are known for mucoadhesive properties but suffer from poor chemical definition and solubility, while the chemical synthesis of polysaccharides is challenging with few reported examples of synthetic carbohydrate polymers with engineered-in ionic functionality. We report the design, synthesis, and evaluation of a synthetic, cationic, enantiopure carbohydrate polymer inspired by the structure of chitosan. These water-soluble, cytocompatible polymers are prepared via an anionic ring-opening polymerization of a bicyclic ß-lactam sugar monomer. The synthetic method provides control over the site of amine functionalization and the length of the polymer while providing narrow dispersities. These well-defined polymers are mucoadhesive as documented in single-molecule scale (AFM), bulk solution phase (FRAP), and ex vivo tissue experiments. Polymer length and functionality affects bioactivity as long, charged polymers display higher mucoadhesivity than long, neutral polymers or short, charged polymers.