Enzyme-triggered- and tumor-targeted delivery with tunable, methacrylated poly(ethylene glycols) and hyaluronic acid hybrid nanogels.

Enzyme-responsive polymeric-based nanostructures are potential candidates for serving as key materials in targeted drug delivery carriers. However, the major risk in their prolonged application is fast disassembling of the short-lived polymeric-based structures. Another disadvantage is the limited accessibility of the enzyme to the moieties that are located inside the network. Here, we report on a modified environmentally responsive and enzymatically cleavable nanogel carrier that contains a hybrid network. A properly adjusted volume phase transition (VPT) temperature allowed independent shrinking of a) poly(ethylene glycol) methyl ether methacrylate (OEGMA) with di(ethylene glycol) and b) methyl ether methacrylate (MEO2MA) part of the network, and the exposition of hyaluronic acid methacrylate (MeHa) network based carboxylic groups for its targeted action with the cellular based receptors. This effect was substantial after raising temperature in typical hyperthermia-based treatment therapies. Additionally, novel tunable NGs gained an opportunity to store- and to efficient-enzyme-triggered release relatively low but highly therapeutic doses of doxorubicin (DOX) and mitoxantrone (MTX). The controlled enzymatic degradation of NGs could be enhanced by introducing more hyaluronidase enzyme (HAdase), that is usually overexpressed in cancer environments. MTT assay results revealed effective cytotoxic activity of the NGs against the human MCF-7 breast cancer cells, the A278 ovarian cancer cells and also cytocompatibility against the MCF-10A and HOF healthy cells. The obtained tunable, hybrid network NGs might be used as a useful platform for programmed delivery of other pharmaceuticals and diagnostics in therapeutic applications.

Recent Advances in Degradable Hybrids of Biomolecules and NGs for Targeted Delivery.

Recently, the fast development of hybrid nanogels dedicated to various applications has been seen. In this context, nanogels incorporating biomolecules into their nanonetworks are promising innovative carriers that gain great potential in biomedical applications. Hybrid nanogels containing various types of biomolecules are exclusively designed for: improved and controlled release of drugs, targeted delivery, improvement of biocompatibility, and overcoming of immunological response and cell self-defense. This review provides recent advances in this rapidly developing field and concentrates on: (1) the key physical consequences of using hybrid nanogels and introduction of biomolecules; (2) the construction and functionalization of degradable hybrid nanogels; (3) the advantages of hybrid nanogels in controlled and targeted delivery; and (4) the analysis of the specificity of drug release mechanisms in hybrid nanogels. The limitations and future directions of hybrid nanogels in targeted specific- and real-time delivery are also discussed.

Switchable conformational changes of DNA nanogel shells containing disulfide-DNA hybrids for controlled drug release and efficient anticancer action.

Oligonucleotide strands containing dithiol (-SS-) groups were used as the co-crosslinkers in PNIPA-AAc based nanogels (NGs). They hybridized with PEG-oligonucleotides introduced into the gels. The specific DNA hybrid formed in the nanogel/nanocarrier was involved in highly efficient accumulation of intercalators. The presence of -SS- groups/bridges improved the storing efficiency of doxorubicin (Dox) in DNA hybrids by 53, 40 and 20% compared to regular, single stranded and regular double stranded DNA crosslinkers, respectively. The explicit arrangement of the hybrids in the carrier enabled their reduction by glutathione and an effective cancer treatment while the side toxicity could be reduced. Compared to the NGs with traditional crosslinkers and those containing typical dsDNA-based hybrids, an improved, switchable and controlled drug release occurred in the novel NGs. Since the novel NGs can release the oligonucleotide strands during their degradation, this gives an opportunity for a combined drug-gene therapy.

A degradable nanogel drug carrier crosslinked with three-oligonucleotide hybrids for two-way drug release in mild and high hyperthermia treatment.

Three-segment oligonucleotide hybrids were introduced as crosslinkers to a PNIPA-AAc nanonetwork. The obtained nanogels could be specifically transformed and degraded. The specific architecture of the presented carrier aims at achieving effective cancer treatment with reduced side toxicity. As a result, compared to the gels with regular crosslinkers, the drug release could be independently realized by (a) changing the structure of the gel net and conformation of DNA hybrids in an oscillating way and (b) degradation of DNA crosslinkers by denaturation. The hydrodynamic diameter and zeta potential of the nanogels were examined as a function of T and pH. The presence of a DNA helix in the nanogels led to a substantial increase, of nearly three times, in the storing efficiency of the selected anticancer drug compared to the nanogels with regular crosslinkers. Moreover, the nanogels allowed 98% drug release efficiency at high hyperthermic and 70% at mild hyperthermic conditions. The effectiveness of cytotoxicity of insulinoma cells was better compared to free doxorubicin. Since in the proposed approach, in addition to the drug, the third DNA strand can be also liberated, this opens new possibilities in development of gene therapies. This novel biocompatible carrier exhibits enhanced drug loading, possesses tunable and degradable properties under hyperthermic conditions and offers controlled release of the drug.

Electrochemical examination of ability of dsDNA/PAM composites for storing and releasing of doxorubicin.

Composites consisting of ss- and ds-DNA strands and polyacrylamide (PAM) hydrogel have been synthesized. DNA was entrapped non-covalently. The obtained DNA biomaterial exhibited a strong increase in guanine and adenine anodic currents when temperature reached the physiological level. This increase was related to the unique oligonucleotide structural changes in the composite. The structural alterations in the PAM lattices were employed for the release of the drug accumulated in the composite. Doxorubicin (Dox) was selected as the drug; it was accumulated by intercalation to dsDNA and was slowly released from the dsDNA/PAM system by using a minor temperature increase (up to 40÷45 °C) as it is routinely done in hyperthermia. The applied release temperature was either constant or oscillating. The binding strength, the rate of Dox release and the properties of the composite were examined using voltammetry, SEM and ICP-MS.

Hydrogel Nanofilaments via Core-Shell Electrospinning.

Recent biomedical hydrogels applications require the development of nanostructures with controlled diameter and adjustable mechanical properties. Here we present a technique for the production of flexible nanofilaments to be used as drug carriers or in microfluidics, with deformability and elasticity resembling those of long DNA chains. The fabrication method is based on the core-shell electrospinning technique with core solution polymerisation post electrospinning. Produced from the nanofibers highly deformable hydrogel nanofilaments are characterised by their Brownian motion and bending dynamics. The evaluated mechanical properties are compared with AFM nanoindentation tests.