Multi-Functional Nanogels as Theranostic Platforms: Exploiting Reversible and Nonreversible Linkages for Targeting, Imaging, and Drug Delivery

Abstract

Nanogels that are amenable to facile multi-functionalization with imaging, therapeutic, and targeting agents are attractive theranostic platforms for addressing challenges in conventional diagnostics and therapy. In this work, reactive copolymers containing poly(ethylene glycol), maleimide, and pendant hydroxyl groups as side chains are used to construct nanogels by employing their thermoresponsive self-assembly in aqueous media. Subsequent cross-linking of these nanosized aggregates with dithiols using thiol-maleimide chemistry yields nanogels containing maleimide, thiol, and hydroxyl groups. The hydroxyl groups are readily activated to N-hydroxysuccinimide based carbonates that undergo conjugation with amine-containing molecules through carbamate linkage under mild conditions. As a demonstration of multi-functionalization, the maleimide, thiol, and activated carbonate groups were functionalized with a thiol-containing cancer cell targeting peptide, a maleimide-containing fluorescent indocyanine Cy5 dye, and an anticancer drug doxorubicin, respectively. It was observed that enhanced drug release from nanogels occurs under acidic conditions. While the parent nanogel vehicles did not possess any toxicity, drug conjugated constructs with and without targeting group were cytotoxic against MDA-MB-231 breast cancer cells. The cyclic peptide containing targeted nanogel exhibited slightly higher cytotoxicity than its counterpart devoid of any targeting group. Furthermore, higher level of drug internalization into MDA-MB-231 cells was observed for the targeting group containing construct. It can be envisioned that facile fabrication and multi-functionalization of these reactive nanogels simultaneously through nonreversible and reversible linkages offers a modular platform that can be configured as a theranostic agent for addressing challenges in conventional therapy of various diseases.

Polymers and Polymer Nanocomposites for Cancer Therapy

“…Copolymers containing PEG, maleimide, and pendant hydroxyl groups as side chains are often used to produce nanogels [107].…”

Preparation of a novel injectable in situ-gelling nanoparticle with applications in controlled protein release and cancer cell entrapment

“…18 To overcome these concerns, a series of thermosensitive polymers or nanoparticles based on oligo(ethylene glycol) methacrylate (OEGMA) with different ethylene glycol chain lengths have been developed. [28][29][30][31] By copolymerization of OEGMA monomers with different length of ethylene glycol chain, the as-prepared nanoparticles have a wide range of LCST, similar to those of PNIPAM or PEG-based hydrogels. [28][29][30][31] For instance, a copolymer hydrogel based on di(ethylene glycol) methacrylate (MEO 2 MA, n ¼ 2) and OEGMA 475 (mw ¼ 475 g mol À1 , n ¼ 8, 9) has a volume phase transition temperature (VPTT) between 23 C and 90 C. 32 These results support the overall hypothesis of this work that thermally induced gelling system can be made of OEGMA particles.…”

Reactive Precursor Particles as Synthetic Platform for the Generation of Functional Nanoparticles, Nanogels, and Microgels

“…The hydroxyl groups were later modified with NHS to obtain a nanogel with three potential functional groups: a maleimide, a thiol, and an activated carbonate. This allowed the functionalization with a thiol‐containing cancer cell targeting peptide, a maleimide‐containing fluorescent indocyanine Cy5 dye, and the anticancer drug doxorubicin, respectively ( Figure ) . This proves that the combination of different reactive groups given by the range of “click” chemistry reactions into the same colloidal systems opens the possibility to target different applications at the same time.…”

“…Schematic representation reactive precursor nanogels for multifunctionalization. Reproduced with permission . Copyright 2018, American Chemical Society.…”