Use of pH-Active Catechol-Bearing Polymeric Nanogels with Glutathione-Responsive Dissociation to Codeliver Bortezomib and Doxorubicin for the Synergistic Therapy of Cancer

Abstract

Synergistic therapy holds promising potential in cancer treatment. Here, the inclusion of catechol moieties, a disulfide cross-linked structure, and pendent carboxyl into the network of polymeric nanogels with glutathione (GSH)-responsive dissociation and pH-sensitive release is first disclosed for the codelivery of doxorubicin (DOX) and bortezomib (BTZ) in synergistic cancer therapy. The pendent carboxyl groups and catechol moieties are exploited to absorb DOX through electrostatic interaction and conjugate BTZ through boronate ester, respectively. Both electrostatic interactions and boronate ester are stable at neutral or alkaline pH, while they are instable in an acidic environment to further recover the activities of BTZ and DOX. The polymeric nanogels possess a superior stability to prevent the premature leakage of drugs in a physiological environment, while their structure is destroyed in response to a typical endogenous stimulus (GSH) to unload drugs. The dissociation of the drugloaded nanogels accelerates the intracellular release of DOX and BTZ and further enhances the therapeutic efficacy. In vitro and in vivo investigations revealed that the dual-drug loaded polymeric nanogels exhibited a strong ability to suppress tumor growth. This study thus proposes a new perspective on the production of multifunctional polymeric nanogels through the introduction of different functional monomers.

Dual drug delivery collagen vehicles for modulation of skin fibrosis in vitro

“…In this context, the use of multi-cargo delivery vehicles [1,2] for a wide variety of clinical indications (e.g. ophthalmology [3], cancer [4], diabetic wounds [5], orthopaedics [6]) has been proposed. Data to-date, clearly illustrate the superiority of multi-molecular delivery systems over traditional mono-molecular administration approaches with respect to improved therapeutic effect, reduced systemic toxicity and lowered treatment cost [7][8][9][10].…”

Polyzwitterionic Nanogels for Controlled and Sustained Release of Bicarbonate Anions for Treatment of Metabolic Acidosis

“…We anticipated that because of their smaller size and capacity to make stronger ionic interactions with the cationic centers of the polyzwitterion, hydroxide ions from water might potentially exchange bicarbonate ions. On the contrary, anion transport from nanogel polymeric matrix to release media is majorly governed by an amalgamation of factors, including anion diffusion and swelling of the polymer . The interplay of these events causes the controlled and sustained release, as indicated in Figure for PZNGs.…”

“…On the contrary, anion transport from nanogel polymeric matrix to release media is majorly governed by an amalgamation of factors, including anion diffusion and swelling of the polymer. 58 The interplay of these events causes the controlled and sustained release, as indicated in Figure 5 for PZNGs.…”

Polyzwitterionic Nanogels for the Controlled and Sustained Delivery of NO and H2S

“…It was anticipated that the exchange of NO 2 – ions from nanogels would be facilitated by the smaller size of hydroxide ions and their capacity to create stronger ionic connections with cationic centers in the polyzwitterion (Scheme S2). Also, anion diffusion and polymer swelling, among other parameters, control the release of anions from the nanogel polymeric matrix into the release media . Simultaneously, in the release medium, due to the presence of metal salts/acids, eventually these NO 2 – anions convert into NO.…”

“…Also, anion diffusion and polymer swelling, among other parameters, control the release of anions from the nanogel polymeric matrix into the release media. 51 Simultaneously, in the release medium, due to the presence of metal salts/acids, eventually these NO 2 − anions convert into NO. The interplay of these events causes controlled and sustained release, as inferred from the release profiles.…”