The impact of protons on metallic nanoparticles (MNPs) produces the potent release of MNP-induced secondary electrons and characteristic x-rays. To determine the ability of secondary radiations to enhance proton treatment, the therapeutic irradiation of tumors was investigated in mice receiving 100-300 mg MNPs/kg intravenously prior to single dose, 10-41 Gy, proton irradiation. A proton beam was utilized to irradiate nanoparticles with a single Bragg peak set to occur inside a tumor volume (fully absorbed) or to occur after the beam had traversed the entire body. The dose-dependent increase in complete tumor regression (CTR) was 37-62% in the fully-absorbed irradiation group or 50-100% in the traversing irradiation group, respectively, compared with the proton-alone control mice (p < 0.01). One year survival was 58-100% versus 11-13% proton alone. The dose-dependent increase of intracellular reactive oxygen species level was 12-36% at 10 Gy compared with the proton-alone control cell. Therapeutic effective drug concentration that led to 100% CTR with a proton dose of 31 Gy was measured either 41 µg Au/g tissue or 59 µg Fe/g tissue. MNP-based proton treatment increased not only percent CTR and survival in vivo but also ROS generation in vitro, suggesting tumor dose enhancement from secondary radiation as one potent pathway of therapeutic enhancement.

Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml(-1). With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation-only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg(-1) body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 µg g(-1) tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases.

In this work, antioxidant hydrogels were prepared by the construction of an interpenetrating chitosan network and functionalization with gallic acid. The poly(2-hydroxyethyl methacrylate) p(HEMA)-based hydrogels were first synthesized and subsequently surface-modified with an interpenetrating polymer network (IPN) structure prepared with methacrylamide chitosan via free radical polymerization. The resulting chitosan-IPN hydrogels were surface-functionalized with gallic acid through an amide coupling reaction, which afforded the antioxidant hydrogels. Notably, gallic-acid-modified hydrogels based on a longer chitosan backbone exhibited superior antioxidant activity than their counterpart with a shorter chitosan moiety; this correlated to the amount of gallic acid attached to the chitosan backbone. Moreover, the surface contact angles of the chitosan-modified hydrogels decreased, indicating that surface functionalization of the hydrogels with chitosan-IPN increased the wettability because of the presence of the hydrophilic chitosan network chain. Our study indicates that chitosan-IPN hydrogels may facilitate the development of applications in biomedical devices and ophthalmic materials.

Purpose: Continuous monitoring of elevated intraocular pressure and timely drug delivery for successful treatment of glaucoma are necessary to reduce intraocular pressure (IOP), which shows wide variations across the circadian pattern and in response to medication. This in vivo study presents a new contact lens-based method of optical IOP measurement or temperature-triggered drug elution. Methods: A contact lens with moiré patterns of concentric circles measures the changes in eyeball diameter of a rabbit glaucoma model due to changes in IOP by superimposing a camera-captured image onto the micro pattern of the contact lens with a computer-assisted virtual reference image. Drug elution from the nanoporous bicontinuous microemulsion contact lens (BME-CL) into the eye of the rabbit was triggered by a temperature-responsive nanogel drug carrier. Results: The moiré pattern change on the contact lens was proportional to the IOP increase in the rabbit eye either ex vivo or in vivo and was also correlated with imaging-based alterations in the anterior chamber angle at a range of IOP values (3–40 mm Hg). The cumulative drug absorbed reached as high as 10.6 µg/mL aqueous humor until 7 days after wearing the BME-CL, and a 33% decrease in IOP was observed at 3 hours after drug elution. Conclusions: The results suggest that continuous measurement and treatment of elevated IOP are feasible using moiré pattern-inscribed and thermosensitive drug-eluting contact lenses, respectively. Translational Relevance: Pressure-sensing or thermosensitive contact lenses enable monitoring IOP or drug release triggered by body temperature for the treatment of glaucoma patients.