Hyaluronic Acid–Polyethyleneimine Nanogels for Controlled Drug Delivery in Cancer Treatment

Abstract

The emulsion/evaporation method represents a pivotal approach to synthesize nanogels for controlled drug delivery. However, this strategy is constrained to the use of at least one polymer characterized by a phase-selective solubility in organic or aqueous solutions. Consequently, the formulation of nanoscaffolds based solely on hydrophilic polymers is not feasible by this approach, limiting the applicability of the technique. This work shows an innovative emulsion-based strategy, where two polymers insoluble in water-immiscible organic solvents, hyaluronic acid (HA) and polyethyleneimine (PEI), chemically crosslink to produce nanogels. The procedure exploits the interfacial interactions and the coalescence phenomena occurring in a surfactant-free mixed emulsion, composed of HA and PEI aqueous solutions as dispersed phases and a neat organic solvent as the continuous phase. Our method allows us to obtain HA–PEI nanogels characterized by low polydispersity, good colloidal stability, and high batch-to-batch reproducibility. The synthesized nanoscaffolds were validated as nanocarriers for the controlled release of doxorubicin in ovarian cancer, showing a sustained drug release profile (up to 15 days), which enhanced the therapeutic effects compared to the drug administration in the free form. In particular, through an in vitro assay with a CD44 blocking/neutralizing antibody, we showed that the hyaluronan receptor was involved in the nanogel internalization process, suggesting that our nanogel formulation, obtained through a surfactant-free mixed emulsion, is a promising strategy for the design of HA-based nanocarriers for CD44-targeted therapy.

Development of hybrid hydrogel to facilitate knee joint movement with an engineering approach

“…The hydrogel causing the greatest reduction in peak intensity was JF10 (0.2% PEI‐hBN). It was considered that the PEI decoration process act as a bridge between the HA and hBN molecules because of the conjugation of PEI amine groups and HA carboxyl groups 35–37 . It was probably directly proportional to the amount of PEI‐hBN.…”

“…33,34 It can be predicted that the interaction between the amine groups of the PEI decorated hBN particles and the carboxyl groups of HA will act as a bridge between the two molecules. [35][36][37] In hydrogel designs to be injected into the joint, the rheological properties guide an adequate understanding of the mechanism. Numerous studies in the scientific literature in recent years emphasize the importance of the subject.…”

“…Studies have shown that it is possible to use PEI in hBN modification due to the presence of amine groups and their high water solubility 33,34 . It can be predicted that the interaction between the amine groups of the PEI decorated hBN particles and the carboxyl groups of HA will act as a bridge between the two molecules 35–37 …”

Droplet-based microfluidic synthesis of nanogels for controlled drug delivery: tailoring nanomaterial properties via pneumatically actuated flow-focusing junction

“…This could be ascribed to the aliphatic–aromatic stacking which provided a stacked arrangement of the DOX molecules within the NG architecture, characterized by a higher amount of HA compared to NG_0, and delayed the drug release. 75 On the other hand, NG_0 showed a single diffusion regime (ii) due to the larger size, which did not give a net transition between the two diffusion mechanisms: in this case, a higher DOX fraction was reliably encapsulated within NG meshes, and a lower amount of drug adsorbed at the NG surface was subjected to a quick diffusion process.…”

Nanogels as target drug delivery systems in cancer therapy: A review of the last decade

“…2.5.9.3 Hyaluronic acid nanogels for ovarian cancer therapy Limiti et al (2022) designed hyaluronic acid nanogels for ovarian cancer therapy. They applied "a novel emulsion-based strategy" to produce nanogels by chemically cross-linking hyaluronic acid (HA) and polyethyleneimine (PEI).…”