<p>Design of a Novel Theranostic Nanomedicine (III): Synthesis and Physicochemical Properties of Tumor-Targeting Cisplatin Conjugated to a Hydrophilic Polyphosphazene</p>

Abstract

Purpose: A new theranostic nanomedicine involving anticancer-active cisplatin moiety was designed to study its tumor-targeting properties as well as its drug efficacy and toxicity. Methods: A cisplatin carrier polymer was prepared by grafting equimolar polyethylene glycol of a molecular weight of 550 (PEG550) and aminoethanol to the poly(dichlorophosphazene) backbone. Cisplatin was conjugated to the carrier polymer using cis-aconitic acid as a linker. Results: The cisplatin-loaded polyphosphazene, named "Polycisplatin" was found to be amphiphilic in aqueous solution and self-assembled into nanoparticles with an average particle size of 18.6 nm in diameter. The time-dependent organ distribution study of Cy5.5-labeled Polycisplatin in the A549tumor-bearing mice exhibited a high tumor selectivity of Polycisplatin by EPR effect despite the relatively small particle size. In order to compare the in vivo efficacy of Polycisplatin and cisplatin, their xenograft trials were performed using nude mice against the human gastric cell line MKN-28. Polycisplatin exhibited slightly less tumor suppression effect compared with cisplatin at the same dose of 1.95 mg Pt/kg, which is the maximum tolerate dose of cisplatin, but at the higher double dose of 3.9 mg Pt/kg, Polycisplatin exhibited a little better efficacy than cisplatin. Furthermore, mice treated with cisplatin at the dose of 1.95 mg Pt/kg exhibited severe body weight decrease by about 25%, while mice treated with Polycisplatin did not show serious body weight decrease even at its double dose of 3.9 mg Pt/kg. Furthermore, kidney indicators including kidney index, BUN, and creatinine values measured displayed that Polycisplatin is much less nephrotoxic than cisplatin. Conclusion: Nanoparticular Polycisplatin was successfully prepared by conjugating cisplatin to a hydrophilic polyphosphazene carrier polymer using the acid-cleavable cis-aconitic acid. Polycisplatin nanoparticles exhibit excellent tumor-targeting properties by EPR effect. The xenograft trials exhibited excellent antitumor efficacy and reduced systemic toxicity of Polycisplatin.

Bibliometric and visual analysis of nephrotoxicity research worldwide

“…New biomaterials, such as nanoparticles, dendrimers, micelles, liposomes, and nanogels, including nanomedicine, , which could offer more precise pharmacotherapy options with improved safety profiles, especially in cisplatin and antibiotics, could attenuate nephrotoxicity ( Cooper et al, 2014 ; Desai et al, 2022 ). Reports showed that cisplatin conjugated to a polyphosphazene, lipid-coated cisplatin nanoparticle, and cholesterol-tethered platinum II-based nanoparticle could increase the antitumor effect and reduce nephrotoxicity ( Sengupta et al, 2012 ; Guo et al, 2013 ; Patil et al, 2020 ). Similarly, reduced nephrotoxicity was found in paclitaxel, amphotericin B, and cyclosporine-based nanoparticle application ( Wang et al, 2011 ; Guada et al, 2016 ; Liu et al, 2020 ).…”

Ameliorative impacts of polymeric and metallic nanoparticles on cisplatin-induced nephrotoxicity: a 2011–2022 review

“…Although polycisplatin at the dose of 1.95 mg Pt/kg had less tumor suppressive effect than CDDP, it showed a better efficacy than CDDP at higher doses (> 3.9 mg Pt/kg). On the other hand, novel Pt-bisphosphonate polymer-metal complex nanoparticles (Pt-bp-NPs) are another pH sensitive nanoparticles that have led to a fast drug release in acidic extracellular environment of tumor, resulting in less systemic toxicity of cisplatin [ 116 ]. Cisplatin-loaded poly ( l -glutamic acid)-g-methoxy poly ethylene glycol 5 k nanoparticles (PLG-g-mPEG 5 k) are also a pH and temperature sensitive nanoparticle which demonstrate longer blood circulation and reduced Pt accumulation in kidney, so they can decrease cisplatin-caused renal damages [ 117 ].…”

“… -Allowed high-dose chemotherapy -Decreased: the durability of the drug in the kidney [ 114 ] Nanoparticles functionalized with folate (CP-FA-BSA-NPs) 134.53 −37.66 Balb/c mice (5 mg/kg of CDDP in CP-FA-BSA-NPs) (Tail-vein injection) -Targeted cisplatin delivery -Decreased: CDDP-induced urea, creatinine, and histopathological damage [ 128 ] PEG grafted-olyphosphazene–cisplatin conjugate (Polycisplatin) 18.6 ICR mice (5, 10, 15 and 20 mg platinum/kg) (i.v.) -Passive targeting by EPR effect -Decreased: CDDP-increased BUN, creatinine, and kidney weight/body [ 116 ] Poly(L-glutamic acid)-g-methoxy poly(ethylene glycol 5 K) nanoparticles Changed based on pH – Kunming mice (5 mg/kg of CDDP) (i.v.) – -Decreased: platinum concentration in kidney [ 117 ] LHRH-modified dextran nanoparticles (Dex-SA-CDDP-LHRH) – – Kunming mice (5 or 10 mg/kg of CDDP) (i.v.)…”

The effect of formulation morphology on stimuli-triggered co-delivery of chemotherapeutic and MRI contrast agents

“…This is because small differences in local properties between a tumor and healthy tissues can permit precise temporal and spatial delivery of therapeutic and diagnostic agents. In an effort to achieve this goal, a variety of systems have been developed responding to stimuli including temperature, ultrasound, magnetic field, light, pH, redox potential, or the presence of specific biomolecules (Chang et al, 2011, Zhao et al, 2015, Lin et al, 2017, Jha et al, 2020, Patil et al, 2020.…”