RESUMO
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.
RESUMO
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
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
Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor-selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy-triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e-aq ) from water radiolysis. The subsequently released tertiary amines can be anti-cancer toxins or readily release functional molecules via 1,6-elimination. This radiotherapy-induced cleavage works successfully in living cells and tumor-bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first-line treatment for over 50 % of cancer patients.
Assuntos
Compostos de Amônio , Neoplasias , Pró-Fármacos , Animais , Liberação Controlada de Fármacos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Pró-Fármacos/químicaRESUMO
Precisely activating chemotherapeutic prodrugs in a tumor-selective manner is an ideal way to cure cancers without causing systemic toxicities. Although many efforts have been made, developing spatiotemporally controllable activation methods is still an unmet challenge. Here, we report a novel prodrug activation strategy using radiotherapy (X-ray). Due to its precision and deep tissue penetration, X-ray matches the need for altering molecules in tumors through water radiolysis. We first demonstrated that N-oxides can be effectively reduced by hydrated electrons (e-aq) generated from radiation both in tubes and living cells. A screening is performed to investigate the structure-reduction relationship and mechanism of the e-aq-mediated reductions. We then apply the strategy to activate N-oxide prodrugs. The anticancer drug camptothecin (CPT)-based N-oxide prodrug shows a remarkable anticancer effect upon activation by radiotherapy. This radiation-induced in vivo chemistry may enable versatile designs of radiotherapy-activated prodrugs, which are of remarkable clinical relevance, as over 50% of cancer patients take radiotherapy.
Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Óxidos , Pró-Fármacos/químicaRESUMO
Metal fluoride nanocrystals are widely used in biomedical studies owing to their unique physicochemical properties. The release of metal ions and fluorides from nanocrystals is intrinsic due to the solubility equilibrium. It used to be considered as a drawback because it is related to the decomposition and defunction of metal fluoride nanocrystals. Many strategies have been developed to stabilize the nanocrystals, and the equilibrium concentrations of fluoride are often <1 mM. Here we make good use of this minimum amount of fluoride and unveil that metal fluoride nanocrystals could effectively induce desilylation cleavage chemistry, enabling controlled release of fluorophores and drug molecules in test tubes, living cells, and tumor-bearing mice. Biocompatible PEG (polyethylene glycol)-coated CaF2 nanocrystals have been prepared to assay the efficiency of desilylation-induced controlled release of functional molecules. We apply the strategy to a prodrug activation of monomethyl auristatin E (MMAE), showing a remarkable anticancer effect, while side effects are almost negligible. In conclusion, this desilylation-induced cleavage chemistry avails the drawback on empowering metal fluoride nanocrystals with a new function of perturbing or activating for further biological applications.
Assuntos
Fluoretos/química , Metais/química , Nanopartículas/química , Compostos de Organossilício/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Polietilenoglicóis/química , SolubilidadeRESUMO
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
Amino acids derivative are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative through displacing its carboxylate by trifluoroborate as a selective ASCT2 marker for cancer imaging. 18F-Ala-BF3 was first evaluated in healthy FVB/N mice in vivo, exhibiting rapid renal clearance with almost negligible uptake in stomach (1.53 ± 0.31%ID/g). Notable uptake was observed in thyroid (3.71 ± 0.49%ID/g, 40 min post injection), of which the uptake was significantly inhibited by co-injection with natural L-alanine. In addition, we further established 18F-Ala-BF3 on a human gastric cancer cell (BGC-823) xenografts bearing mouse model. Dynamic PET-CT scan revealed the optimal time window for tumor imaging, it was between 40 and 60 min post injection, when the BGC-823 xenografts uptake was 5.49 ± 1.47%ID/g ( n = 4), and the tumor-to-stomach, tumor-to-blood, tumor-to-muscle, and tumor-to-brain ratios were 3.27 ± 1.53, 3.80 ± 1.48, 3.47 ± 1.48, and 6.20 ± 1.47, respectively.