RESUMO
Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.
Assuntos
Pró-Fármacos , Pró-Fármacos/químicaRESUMO
The C-C coupling of methane (CH4) and carbon dioxide (CO2) to generate acetic acid (CH3COOH) represents a highly atom-efficient chemical conversion, fostering the comprehensive utilization of greenhouse gases. However, the inherent thermodynamic stability and kinetic inertness of CH4 and CO2 present obstacles to achieving efficient and selective conversion at room temperature. Our study reveals that hydroxyl radicals (·OH) and hydrated electrons (eaq-) produced by water radiolysis can effectively activate CH4 and CO2, yielding methyl radicals (·CH3) and carbon dioxide radicals (·CO2-) that facilitate the production of CH3COOH at ambient temperature. The introduction of radiation-synthesized CuO-anchored TiO2 bifunctional catalyst could further enhance reaction efficiency and selectivity remarkably by boosting radiation absorption and radical stability, resulting in a concentration of 7.1 mmol·L-1 of CH3COOH with near-unity selectivity (>95%). These findings offer valuable insights for catalyst design and implementation in radiation-induced chemical conversion.
RESUMO
Radiation-induced cleavage for controlled release inâ vivo is yet to be established. We demonstrate the use of 3,5-dihydroxybenzyl carbamate (DHBC) as a masking group that is selectively and efficiently removed by external radiation inâ vitro and inâ vivo. DHBC reacts mainly with hydroxyl radicals produced by radiation to afford hydroxylation at para/ortho positions, followed by 1,4- or 1,6-elimination to rescue the functionality of the client molecule. The reaction is rapid and can liberate functional molecules under physiological conditions. This controlled-release platform is compatible with living systems, as demonstrated by the release of a rhodol fluorophore derivative in cells and tumor xenografts. The combined benefits of the robust caging group, the good release yield, and the independence of penetration depth make DHBC derivatives attractive chemical caging moieties for use in chemical biology and prodrug activation.
Assuntos
Corantes Fluorescentes/metabolismo , Radical Hidroxila/metabolismo , Neoplasias/metabolismo , Xantonas/metabolismo , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Radical Hidroxila/química , Hidroxilação , Camundongos , Estrutura Molecular , Neoplasias/química , Neoplasias Experimentais/química , Neoplasias Experimentais/metabolismo , Xantonas/químicaRESUMO
Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumor-selective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [18F]FDG (2-[18F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide 18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note, an OxaliPt(IV) linker is designed to construct an [18F]FDG-activated antibody-drug conjugate (Pt-ADC). Sequential injection of Pt-ADC and [18F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation, and we find that [18F]FDG is capable of deprotecting various radiotherapy-removable protecting groups (RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.
Assuntos
Fluordesoxiglucose F18 , Pró-Fármacos , Compostos Radiofarmacêuticos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Pró-Fármacos/química , Animais , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/química , Camundongos , Humanos , Fluordesoxiglucose F18/uso terapêutico , Fluordesoxiglucose F18/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Linhagem Celular Tumoral , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Imunoconjugados/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/administração & dosagemRESUMO
Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody-drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.
Assuntos
Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Humanos , Camundongos , Imunoconjugados/química , Imunoconjugados/farmacologia , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , FemininoRESUMO
Pt(II) drugs are a widely used chemotherapeutic, yet their side effects can be severe. Here we show that the radiation-induced reduction of Pt(IV) complexes to cytotoxic Pt(II) drugs is rapid, efficient and applicable in water, that it is mediated by hydrated electrons from water radiolysis and that the X-ray-induced release of Pt(II) drugs from an oxaliplatin prodrug in tumours inhibits their growth, as we show with nearly complete tumour regression in mice with subcutaneous human tumour xenografts. The combination of low-dose radiotherapy with a Pt(IV)-based antibody-trastuzumab conjugate led to the tumour-selective release of the chemotherapeutic in mice and to substantial therapeutic benefits. The radiation-induced local reduction of platinum prodrugs in the reductive tumour microenvironment may expand the utility of radiotherapy.