Designing Hydrogels for On-Demand Therapy

Abstract

Systemic administration of therapeutic agents has been the preferred approach to treat most pathological conditions, in particular for cancer therapy. This treatment modality is associated with side effects, off-target accumulation, toxicity, and rapid renal and hepatic clearance. Multiple efforts have focused on incorporating targeting moieties into systemic therapeutic vehicles to enhance retention and minimize clearance and side effects. However, only a small percentage of the nanoparticles administered systemically accumulate at the tumor site, leading to poor therapeutic efficacy. This has prompted researchers to call the status quo treatment regimen into question and to leverage new delivery materials and alternative administration routes to improve therapeutic outcomes. Recent approaches rely on the use of local delivery platforms that circumvent the hurdles of systemic delivery. Local administration allows delivery of higher "effective" doses while enhancing therapeutic molecules' stability, minimizing side effects, clearance, and accumulation in the liver and kidneys following systemic administration. Hydrogels have proven to be highly biocompatible materials that allow for versatile design to afford sensing and therapy at the same time. Hydrogels' chemical and physical versatility can be exploited to attain disease-triggered in situ assembly and hydrogel programmed degradation and consequent drug release, and hydrogels can also serve as a biocompatible depot for local delivery of stimuli-responsive therapeutic cargo. We will focus this Account on the hydrogel platform that we have developed in our lab, based on dendrimer amine and dextran aldehyde. This hydrogel is disease-responsive and capable of sensing the microenvironment and reacting in a graded manner to diverse pathologies to render different properties, including tissue adhesion, biocompatibility, hydrogel degradation, and embedded drug release profile. We also studied the degradation kinetics of our stimuli-responsive materials in vivo and analyzed the in vitro conditions under which in vitro-in vivo correlation is attained. Identifying key parameters in the in vivo microenvironment under healthy and disease conditions was key to attaining that correlation. The adhesive capacity of our dendrimer-dextran hydrogel makes it optimal for localized and sustained release of embedded drugs. We demonstrated that it affords the delivery of a range of therapeutics to combat cancer, including nucleic acids, small molecules, and antibody drugs. As a depot for local delivery, it allows a high dose of active biomolecules to be delivered directly at the tumor site. Immunotherapy, a recently blooming area in cancer therapy, may exploit stimuli-responsive hydrogels to impart systemic effects following localized therapy. Local delivery would enable release of the proper drug dose and improve drug bioavailability where needed at the same time creating memory and exerting the therapeutic effect systemically. This Account highlights our perspective on how local and systemic therapies provided by stimuli-responsive hydrogels should be used to impart more precise, long-lasting, and potent therapeutic outcomes.

Figure 1.

Potential treatment approaches. The current gold standard, systemic therapy to elicit local effects, is suboptimal in treating primary solid tumors. The use of local platforms to elicit local effects or to induce systemic effects may circumvent the drawbacks of systemic therapies.

Figure 2.

Passive versus active tumor targeting using nanoparticles. Passive tumor targeting is accomplished by extravasation of nanoparticles via the EPR effect. Active targeting takes advantage of the characteristics of the tumor microenvironment, such as overexpressing cell-surface receptors, to enhance accumulation of nanoparticles at the tumor site. Adapted with permission from ref . Copyright 2015 Elsevier.

Figure 3.

Dendrimer−dextran reaction scheme. Dextran molecules can react with amines on the surface of the tissue and the dendrimer simultaneously to provide adhesion and cohesion, respectively. The labile nature of imine bonds makes this hydrogel biodegradable.

Figure 4.

Stimuli-responsive hydrogels for eliciting local therapeutic effects. Rational material design allows for disease-triggered in situ material assembly, degradation that drives drug release, and hydrogel-embedded responsive cargo.

Figure 5.

Dendrimer−dextran presents disease-responsive adhesion. (A) Collagen I immunostaining (green) in (i) healthy and (ii) neoplastic tissues (red). (B) High correlation is achieved between collagen and amine density en face (R² = 0.99, P < 0.05). (C) Amine density on the colon serosal layer was assessed by aldehyde-coated fluorescent microspheres (green) in (i) healthy and (ii) cancerous rat tissues (red), and dendrimer−dextran adhesive (green) morphology on the colon serosal layer was assessed when applied to (iii) healthy and (iv) neoplastic rat tissues (red). (D) Maximum load at failure measured for healthy and cancerous tissues. Adapted with permission from ref . Copyright 2015 AAAS.

Figure 6.

Tissue-type chemistry triggers different degradation profiles. (A) Tissue surface chemistry affects material degradation. (B) Snapshots of material (green) degradation as a function of the tissue (red) to which it was applied. Adapted from ref . Copyright 2012 American Chemical Society.

Figure 7.

In vivo degradation profile is site-dependent. (A) In vivo erosion at target sites (subcutaneous (SC), intraperitoneal (IP), and intramuscular (IM)) is site-dependent. (B) In vivo erosion profiles were used to infer physiologically relevant conditions that linearly are correlated with the in vivo erosion. (C) A correlation between the erosion profiles in vitro and in vivo was achieved with varying volumes of solution with the physiological collagenase concentration. Adapted with permission from ref . Copyright 2011 Nature Publishing Group.

Figure 8.

(a) Scheme of dark-gold nanobeacons designed to sense and overcome cancer multidrug resistance. (b, c) IVIS tomography imaging of mice xenografted with breast tumors implanted with hydrogels embedded with nanobeacon anti-MRP1 with 5-FU and nanobeacon nonsense with 5-FU. (d) Evaluation of change in tumor size as a function of time after treatment with nanobeacons (n = 5; ***, P < 0.005). (e) Nanobeacon probe signals as functions of time after treatment with hydrogel nanobeacons (n = 5; ***, P < 0.005). Adapted with permission from ref . Copyright 2015 National Academy of Sciences.

Figure 9.

(a) Development of a smart hydrogel−nanoparticle patch for in vivo local gene/drug delivery combined with phototherapy. (b) Quantification of the drug-antibody nanorod and RNAi nanosphere signals from ex vivo tumors and organs from mice treated with triple therapy administered via local implantation of the hydrogel or injected via systemic and intratumoral administrations. (c) Luciferase activity as a measure of the tumor burden (n = 5; ***, P < 0.001). (d) Kaplan−Meier survival curves. Adapted with permission from ref . Copyright 2016 Nature Publishing Group.

Figure 10.

Hydrogel-mediated immunotherapy as local therapy with systemic effects. Natural materials can act as T-cell depots to allow expansion and release prior to implantation to attain passive tumor immunotherapy. Alternatively, synthetic materials can be used to differentiate host’s innate dendritic cells into T cells capable of recognizing tumor cells in an active immunotherapy process.