ABSTRACT
Hypoxia (low-oxygen) is one of the most common characteristics of solid tumours. Exploiting tumour hypoxia to reductively activate Pt(IV) prodrugs has the potential to deliver toxic Pt(II) selectively and thus overcome the systemic toxicity issues of traditional Pt(II) therapies. However, our current understanding of the behaviour of Pt(IV) prodrugs in hypoxia is limited. Here, we evaluated and compared the aryl carbamate fluorogenic Pt(IV) complexes, CisNap and CarboNap, as well as the previously reported OxaliNap, as potential hypoxia-activated Pt(IV) (HAPt) prodrugs. Low intracellular oxygen concentrations (<0.1%) induced the greatest changes in the respective fluorescence emission channels. However, no correlation between reduction under hypoxic conditions and toxicity was observed, except in the case for CarboNap, which displayed significant hypoxia-dependent toxicity. Other aryl carbamate Pt(IV) derivatives (including non-fluorescent analogues) mirrored these observations, where carboplatin(IV) derivative CarboPhen displayed a hypoxia-selective cytotoxicity similar to that of CarboNap. These findings underscore the need to perform extensive structure activity relationship studies on the cytotoxicity of Pt(IV) complexes under normoxic and hypoxic conditions.
Subject(s)
Antineoplastic Agents , Fluorescent Dyes , Prodrugs , Prodrugs/chemistry , Prodrugs/pharmacology , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/chemical synthesis , Drug Design , Cell Line, Tumor , Cell Hypoxia/drug effects , Cell Survival/drug effects , Molecular Structure , Structure-Activity Relationship , Drug Screening Assays, Antitumor , Platinum/chemistry , Platinum/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesisABSTRACT
We report the synthesis of 4-nitrophenyl (4-NP) functionalised Pt(iv) complexes as a colorimetric strategy for monitoring Pt(iv) reduction in aqueous solution. Treatment of each 4-NP functionalised Pt(iv) complex with the biological reductant sodium ascorbate led to a colour change from clear to yellow, which was attributed to the reduction of Pt(iv) to Pt(ii) and simultaneous release of 4-nitroaniline. Trends in reduction profiles and a photocatalysed reduction for each Pt(iv) complex were observed.
ABSTRACT
Achieving a controlled release of several active pharmaceutical ingredients (APIs) remains a challenge for improving their therapeutic effects and reduced their side effects. In the current work, stimulable Drug Delivery Systems (DDS) based on supramolecular hydrogels were designed by combining two APIs featuring anticancer activities, namely the doxorubicin and phenazine 14. In vitro studies revealed promising physicochemical properties for all the investigated API loaded gels. Fluorinated GlycoNucleoLipid (GNF) based supramolecular gels remain stable in the presence of either doxorubicin (Doxo) or phenazine 14 (Phe) as anticancer drugs. Noteworthy, the stiffness of the GNF-based supramolecular gels was enhanced in the presence of both APIs while maintaining their thixotropic properties. We demonstrated that the storage modulus (G') of the GNF gels was increased from 1.3 kPa to 9.3 kPa upon loading of both APIs within the same gels. With a low mechanical stimulation (within the LVR), a passive diffusion out of gels was observed for Dox whereas Phe remained trapped in the GNF gels over several hours. Also, in this work we showed that mechanical stress triggered the release of both Phe and Doxo at different rates.