Cell-Penetrating Hyperbranched Polyprodrug Amphiphiles for Synergistic Reductive Milieu-Triggered Drug Release and Enhanced Magnetic Resonance Signals

Abstract

The rational design of theranostic nanoparticles exhibiting synergistic turn-on of therapeutic potency and enhanced diagnostic imaging in response to tumor milieu is critical for efficient personalized cancer chemotherapy. We herein fabricate self-reporting theranostic drug nanocarriers based on hyperbranched polyprodrug amphiphiles (hPAs) consisting of hyperbranched cores conjugated with reduction-activatable camptothecin prodrugs and magnetic resonance (MR) imaging contrast agent (Gd complex), and hydrophilic coronas functionalized with guanidine residues. Upon cellular internalization, reductive milieu-actuated release of anticancer drug in the active form, activation of therapeutic efficacy (>70-fold enhancement in cytotoxicity), and turn-on of MR imaging (∼9.6-fold increase in T1 relaxivity) were simultaneously achieved in the simulated cytosol milieu. In addition, guanidine-decorated hPAs exhibited extended blood circulation with a half-life up to ∼9.8 h and excellent tumor cell penetration potency. The hyperbranched chain topology thus provides a novel theranostic polyprodrug platform for synergistic imaging/chemotherapy and enhanced tumor uptake.

Novel walnut peptide–selenium hybrids with enhanced anticancer synergism: facile synthesis and mechanistic investigation of anticancer activity

“…Here, size controllable and highly stable WP1-SeNPs hybrids encapsulated in a coherent peptides capping layer were generated by a redox system in the presence of sodium selenite and ascorbic acid (Figure 1). When SeO 3 2-and ascorbic acid reacted in the presence of peptides in aqueous solution, Se was reduced from SeO 3 2-through oxidation-reduction reaction and soon polymerized/ encapsulated with WP1 to form WP1-SeNPs. The strong conjugation and anchoring of peptide molecules on the surface of SeNPs facilitated the size-controlled formation of WP1-SeNPs.…”

“…For example, chemotherapy drugs tend to show non-specific cytotoxicity and will kill not only cancerous tumor cells, but also damage normal tissues. 2,3 In addition, the non-specific distribution, poor water solubility, instability, and the development of multidrug resistance over prolonged usage limit the bioavailability and clinical applications of many anticancer drugs. 4,5 Nanotechnology and nanomaterials owing to their unique optical, electronic, magnetic, photoresponsive, and structural properties have demonstrated immense promise for employing them in tumor-targeted therapy, bio-imaging, and diagnosis.…”

Synthesis and in vivo magnetic resonance imaging evaluation of biocompatible branched copolymer nanocontrast agents

“…Recently, RAFT has been applied in synthesis of classic hyperbranched or core cross-linked star polymer nanocontrast agents, which has demonstrated good control of polymer structure. [36][37][38]44,45 The novel dimethacrylate cross-linker 6 employed incorporates the DO3A macrocycles simultaneously during the branching process ensuring the DO3A macrocycles are …”

“…To date, most polymer nanocontrast agents focus on Gd(III) chelates conjugated onto dendrimers, [16][17][18][19][20][21][22] liposomes, [23][24][25][26][27][28][29][30] micelles, [31][32][33][34][35] core cross-linked star polymers, 36,37 and hyperbranched polymers. [36][37][38] Polymer-based nanoparticle MRI contrast agents have demonstrated optimal pharmacokinetics and circulation half-life, increased tolerance to enzymatic degradation, as well as greater physical and chemical stability which improve their therapeutic value. For example, Liu et al have recently reported 38 that Gd(III) chelates have been conjugated onto hyperbranched polyprodrug amphiphiles which demonstrate prolonged blood circulation with a half-life up to ∼9.8 hours.…”

“…[36][37][38] Polymer-based nanoparticle MRI contrast agents have demonstrated optimal pharmacokinetics and circulation half-life, increased tolerance to enzymatic degradation, as well as greater physical and chemical stability which improve their therapeutic value. For example, Liu et al have recently reported 38 that Gd(III) chelates have been conjugated onto hyperbranched polyprodrug amphiphiles which demonstrate prolonged blood circulation with a half-life up to ∼9.8 hours.…”