Polymer Nanomedicines with Ph-Sensitive Release of Dexamethasone for the Localized Treatment of Inflammation

Abstract

Polymer-drug conjugates have several advantages in controlled drug delivery to inflammation as they can accumulate and release the drug in inflamed tissues or cells, which could circumvent the shortcomings of current therapy. To improve the therapeutic potential of polymer-drug conjugates in joint inflammation, we synthesized polymer conjugates based on N-(2-hydroxypropyl) methacrylamide) copolymers labeled with a near-infrared fluorescent dye and covalently linked to the anti-inflammatory drug dexamethasone (DEX). The drug was bound to the polymer via a spacer enabling pH-sensitive drug release in conditions mimicking the environment inside inflammation-related cells. An in vivo murine model of adjuvant-induced arthritis was used to confirm the accumulation of polymer conjugates in arthritic joints, which occurred rapidly after conjugate application and remained until the end of the experiment. Several tested dosage schemes of polymer DEX-OPB conjugate showed superior anti-inflammatory efficacy. The highest therapeutic effect was obtained by repeated i.p. application of polymer conjugate (3 × 1 mg/kg of DEX eq.), which led to a reduction in the severity of inflammation in the ankle by more than 90%, compared to 40% in mice treated with free DEX.

Nanoplatforms for Targeted Stimuli-Responsive Drug Delivery: A Review of Platform Materials and Stimuli-Responsive Release and Targeting Mechanisms

“…The readers can refer to several reviews for more detailed information on these issues [ 474 , 479 , 480 , 481 ]. Additionally, the pH in inflammation lesions is also reduced; thus, appropriate targeting strategies should be considered to avoid potential systemic toxicity for pH-responsive systems in general [ 482 , 483 ].…”

“…Recent advances include the use of phase-change agents such as PFCs and gas generating agents such as NH 4 HCO 3 , which have small volume until vaporized by ultrasound or reacted at low pH [ 756 , 757 , 758 , 759 ]. However, the difficulties in exclusion and degradation of PFCs raise safety concerns [ 760 , 761 ], and NH 4 HCO 3 may also respond to inflammation tissues with low pH [ 482 , 483 ]. Another potential improvement in ultrasound-responsive DDSs might be enabled by the report of Kwan et al on a nano-cup capable of trapping gas within the cavity [ 762 ].…”

Ibuprofen-Loaded ZnO Nanoparticle/Polyacrylonitrile Nanofibers for Dual-Stimulus Sustained Release of Drugs

“…In a normal tissue environment, the temperature of the skin is about 37 °C; however, under inflammatory conditions, the temperature is higher owing to vasodilation and enhanced tissue metabolism, reaching up to 42 °C . The pH was 6.5 and 7.4 in an normal and inflammatory tissue environment, respectively . The temperature of the shaking incubator and the pH of the PBS solution were changed to set up four groups of parallel experiments [(A) 37 °C, pH = 6.5; (B) 37 °C, pH = 7.4; (C) 42 °C, pH = 6.5; and (D) 42 °C, pH = 7.4] for the investigation of the temperature and pH response drug release property of ZnO-ibuprofen/PAN nanofibers.…”

“…56 The pH was 6.5 and 7.4 in an normal and inflammatory tissue environment, respectively. 57 The temperature of the shaking incubator and the pH of the PBS solution were changed to set up four groups of parallel experiments [(A) 37 °C, pH = 6.5; (B) 37 °C, pH = 7.4; (C) 42 °C, pH = 6.5; and (D) 42 °C, pH = 7.4] for the investigation of the temperature and pH response drug release property of ZnO-ibuprofen/PAN nanofibers.…”

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

“…Recently, linear pHPMAs have also been employed for the targeted delivery of anti-inflammatory drug dexamethasone [ 41 , 42 ]. Preferable accumulation of dexamethasone carrying nanomedicines within the inflamed tissue was detected, showing the potential of these nanomedicines to be passively accumulated within the inflammation tissue upon intravenous or intraperitoneal injection.…”