Gadolinium(III) Coordinated Theranostic Polymer for Proficient Sequential Targeting–Combinational Chemotherapy and T₁ Weighted Magnetic Resonance Imaging

Abstract

The combination therapy where a single delivery agent codelivers multiple drugs at the targeted site has become a promising strategy to achieve synergistic chemotherapeutic effect leading to the suppression of cancer cell drug resistance capability. Herein, we developed a theranostic polymer CP PG MT Gd that can sequentially target folate receptors (FR) onto cancer cell apical membrane at an early phase and exhibited late phase combinational chemotherapy through topoisomerase-I (TOPO-I) and dihydrofolate reductase (DHFR) inhibition synergistically, which resulted in inhibition of nucleic acid biosynthesis. This dual-acting self-targeted CP PG MT Gd polymer could effectively track the loaded chemotherapeutic agents (camptothecin–methotrexate) through MRI-tomography and eventually played a decisive role for subsequent dose-determination in real-time.A thorough comparative investigation on FR-targeting competence of CP PG MT Gd was executed with a folic acid (FOL) conjugated CP PG FL Gd (targeted system) and a nontargeted CP PG Gd polymers using human cervical cancer, HeLa (high FR-expression), and breast cancer MCF-7 (low FR-expression) cell lines. The incorporated Gd­(III) chelate-complex in the CP PG MT Gd theranostic polymer displayed remarkable T 1 weighted MRI-proficiency with longitudinal specific relaxivity constant, r 1 = 21.85 mM–1 S–1. Therefore, the MRI-tracking proficiency and sequential targeting–chemotherapy switchable CP PG MT Gd theranostic system opened the way for precise multidrug codelivery at cancer site that might have attractive potential for diagnosis and decisive dose-determination in clinical implication.

Nanoscale Contrast Agents for Magnetic Resonance Imaging: A Review

“…Combinational therapy has been widely explored for targeted cancer treatment to improve the chemotherapeutic effect and efficiently suppress the cancer cells with drug-resistance capabilities. , A novel theranostic polymer was designed for the targeted delivery of camptothecin using the Gd­(III) chelate complex and methotrexate, with directing ability toward folate receptors on a cancer cell apical membrane (Figure ). The designed polymer could be applied for the treatment and detection of cancers at early stages and demonstrated late-phase combinational chemotherapy via the synergistic inhibition of topoisomerase I and dihydrofolate reductase, providing inhibitory effects against the biosynthesis of nucleic acid. This nanosystem efficiently tracked camptothecin–methotrexate chemotherapeutic drugs via MRI tomography, thereby performing a significant role for the dose determination in a real-time manner.…”

“…This nanosystem efficiently tracked camptothecin–methotrexate chemotherapeutic drugs via MRI tomography, thereby performing a significant role for the dose determination in a real-time manner. The applied Gd­(III) chelate complex in this theranostic system exhibited high T 1 -weighted MRI proficiency with a longitudinal precise relaxivity constant ( r 1 was ∼21.85 mM –1 s –1 ), thus paving the way for both targeted anticancer delivery and specific cancer diagnosis with clinical potentials …”

“…ER: endoplasmic reticulum. Reproduced with permission from ref . Copyright 2022 American Chemical Society.…”

Unique Random-Block Polymer Architecture for Site-Specific Mitochondrial Sequestration-Aided Effective Chemotherapeutic Delivery and Enhanced Fluorocarbon Segmental Mobility-Facilitated 19F Magnetic Resonance Imaging

“…Early stage detection and simultaneous requisite treatment at the targeted site are prime needs in cancer therapy. Magnetic resonance imaging (MRI) emerged as a powerful diagnostic tool for tracking the drug delivery system and its continuous therapeutic monitoring in a non-invasive manner, unlike positron emission tomography, single-photon emission computed tomography, and computed tomography. − Though 1 H MRI contrast agents offer visualization of anatomy in the body due to high spatial resolution and deep tissue penetration but still present some disadvantages like limited contrast, toxicity, confusion at hypointense area due to some pathogenic conditions, and so forth. − Therefore, direct visualization of MRI active heteronuclear atoms in the drug delivery system depicts the perfect anatomical details and system tracking. 19 F MRI is a promising strategy, where the 19 F nucleus generates the magnetic resonance (MR) signal to overcome those limitations due to several properties: − (I) 100% natural abundance with 1/2 nuclear spin-like 1 H; (II) high relative sensitivity (83% of 1 H); (III) low endogenous background signal; (IV) vast chemical shift (>350 ppm); (V) resonance frequency (94% of 1 H); and (VI) the gyromagnetic ratio very close to hydrogen (40.08 MHz/T, 94% of 1 H).…”

Iron(III) Coordinated Theranostic Polyprodrug with Sequential Receptor-Mitochondria Dual Targeting and T1-Weighted Magnetic Resonance Imaging Potency for Effective and Precise Chemotherapy

“…Along with the precise and effective mitochondrial drug delivery to cancer cells, monitoring the area of interest is crucial for potential cancer therapy. Therefore, polymer-based theranostic systems exert enormous attention because of their dual capability of treatment and diagnosis together in a single system. − Moreover, these polymer nanomedicines possess many other amenities like drug solubility, unique geometry, site-specific biodistribution profile, and the enhanced permeation and retention (EPR) effect. − Magnetic resonance imaging (MRI) has already emerged as a potential imaging technique in the clinic. It provides clear insight images of the affected area without using high-energy electromagnetic waves or any radioactive agents like PET, SPECT, and CT. − Although several MRI active complexes of gadolinium are available in the clinic, the nephrotoxicity issues make a problem to the patient’s health. − Moreover, The long MRI scan is indispensable for these complexes.…”