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Journal of Nanobiotechnology Jan 2022A widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs... (Review)
Review
A widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs extremely uplift the physicochemical properties, site-specificity, and antitumor activities of therapeutic agents while reducing systemic toxicity. Although great perspectives have been summarized in the progress of prodrug-based nanoplatforms, no attention has been paid to emphasizing the rational design of small-molecule lipidic prodrugs (SLPs). With the aim of outlining the prospect of the SLPs approach, the review will first provide an overview of conjugation strategies that are amenable to SLPs fabrication. Then, the rational design of SLPs in response to the physiological barriers of chemotherapeutic agents is highlighted. Finally, their biomedical applications are also emphasized with special functions, followed by a brief introduction of the promising opportunities and potential challenges of SLPs-based drug delivery systems (DDSs) in clinical application.
Topics: Antineoplastic Agents; Drug Delivery Systems; Lipids; Nanomedicine; Prodrugs
PubMed: 35073914
DOI: 10.1186/s12951-022-01257-4 -
Chemical & Pharmaceutical Bulletin 2018In recent years, nucleic acid-based drug therapeutics have gained considerable attention for their potential in the treatment of various diseases. However, their... (Review)
Review
In recent years, nucleic acid-based drug therapeutics have gained considerable attention for their potential in the treatment of various diseases. However, their therapeutic value is greatly hindered by the challenge of delivering them into cells. One possible strategy to improve cellular uptake is the use of "prodrug-type oligonucleotide medicine" in which negatively charged phosphodiester moieties are masked by bio-labile protecting groups. In this review, we describe our recent studies related to bio-labile protecting groups for phosphodiester moieties in the development of prodrug-type oligonucleotide medicines.
Topics: Gene Transfer Techniques; Humans; Oligonucleotides; Prodrugs; Surface Properties
PubMed: 29386465
DOI: 10.1248/cpb.c17-00696 -
International Journal of Molecular... Feb 2022Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to...
Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A (PLA) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA.
Topics: Cyclosporine; Humans; Inflammatory Bowel Diseases; Phospholipases A2; Phospholipids; Prodrugs
PubMed: 35269813
DOI: 10.3390/ijms23052673 -
Acta Biomaterialia Mar 2022L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the...
L-377,202 prodrug consists of doxorubicin (Dox) conjugated to a prostate-specific antigen (PSA) peptide substrate that can be cleaved by enzymatically active PSA at the tumor site. Despite the initial promise in phase I trial, further testing of L-377,202 (herein called Dox-PSA) was ceased due to some degree of non-specific activation and toxicity concerns. To improve safety of Dox-PSA, we encapsulated it into low temperature-sensitive liposomes (LTSL) to bypass systemic activation, while maintaining its biological activity upon controlled release in response to mild hyperthermia (HT). A time-dependent accumulation of activated prodrug in the nuclei of PSA-expressing cells exposed to mild HT was observed, showing that Dox-PSA was efficiently released from the LTSL, cleaved by PSA and entering the cell nucleus as free Dox. Furthermore, we have shown that Dox-PSA loading in LTSL can block its biological activity at 37°C, while the combination with mild HT resulted in augmented cytotoxicity in both 2D and 3D PC models compared to the free Dox-PSA. More importantly, Dox-PSA encapsulation in LTSL prolonged its blood circulation and reduced Dox accumulation in the heart of C4-2B tumor-bearing mice over the free Dox-PSA, thus significantly improving Dox-PSA therapeutic window. Finally, Dox-PSA-loaded LTSL combined with HT significantly delayed tumor growth at a similar rate as mice treated with free Dox-PSA in both solid and metastatic PC tumor models. This indicates this strategy could block the systemic cleavage of Dox-PSA without reducing its efficacy in vivo, which could represent a safer option to treat patients with locally advanced PC. STATEMENT OF SIGNIFICANCE: This study investigates a new tactic to tackle non-specific cleavage of doxorubicin PSA-activatable prodrug (L-377,202) to treat advanced prostate cancer. In the present study, we report a nanoparticle-based approach to overcome the non-specific activation of L-377,202 in the systemic circulation. This includes encapsulating Dox-PSA in low temperature-sensitive liposomes to prevent its premature hydrolysis and non-specific cleavage. This class of liposomes offers payload protection against degradation in plasma, improved pharmacokinetics and tumor targeting, and an efficient and controlled drug release triggered by mild hyperthermia (HT) (∼42°C). We believe that this strategy holds great promise in bypassing any systemic toxicity concerns that could arise from the premature activation of the prodrug whilst simultaneously being able to control the spatiotemporal context of Dox-PSA cleavage and metabolism.
Topics: Animals; Cell Line, Tumor; Doxorubicin; Hot Temperature; Humans; Liposomes; Male; Mice; Prodrugs; Prostatic Neoplasms
PubMed: 34954416
DOI: 10.1016/j.actbio.2021.12.019 -
Theranostics 2018The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable...
The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics. : We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC. The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor-targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib a cleavable disulfide linker. Furthermore, the integration of the near-infrared -BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine . : PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug. PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells. We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy. The results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects. Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens. The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h. Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models. The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC.
Topics: Animals; Apoptosis; Biopsy; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Fluorescence; Gefitinib; Humans; Infrared Rays; Lung; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Polyamines; Prodrugs; Proto-Oncogene Proteins c-akt
PubMed: 29721074
DOI: 10.7150/thno.24041 -
Journal of Pharmacological Sciences Jun 2023AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the...
OBJECTIVE
AST-3424 is a novel specific aldo-keto reductase 1C3 (AKR1C3) prodrug that releases a DNA alkylating reagent upon reduction by AKR1C3. This study aimed to evaluate the efficacy and safety of AST-3424 in patient-derived tumor xenograft (PDTX) model and orthotopic model against hepatocellular carcinoma (HCC).
MATERIALS AND METHOD
PDTX models derived from three HCC patients and orthotopic mice models using HepG2 cells were developed. The mice were treated with AST-3424 alone or combined with other drugs (oxaliplatin, apatinib, sorafenib and elemene in PDTX models, oxaliplatin and 5- fluorouracil in orthotopic models). The tumor volume and weight, as well as the mice weight were assessed. The liver tumor and transplanted tumor were removed for histological, immunohistochemical and Western blot detection in orthotopic model experiments.
RESULTS
AST-3424 could inhibit tumor growth in HCC PDTX models and orthotopic models, with no difference in safety compared with other marketed drugs, and the drug combination did not increase toxicity. The inhibitory effect of combination treatment was more obvious than which used alone. The reduction of AKR1C3 expression was negatively correlated with AST-3424 dose.
CONCLUSION
AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Liver Neoplasms; Prodrugs; Oxaliplatin; Cell Line, Tumor; Xenograft Model Antitumor Assays; Antineoplastic Agents; Aldo-Keto Reductase Family 1 Member C3
PubMed: 37169481
DOI: 10.1016/j.jphs.2023.03.004 -
Theranostics 2021Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic...
Photodynamic therapy (PDT) has emerged as one of the most up-and-coming non-invasive therapeutic modalities for cancer therapy in rencent years. However, its therapeutic effect was still hampered by the short life span, limited diffusion distance and ineluctable depletion of singlet oxygen (O), as well as the hypoxic microenvironment in the tumor tissue. Such problems have limited the application of PDT and appropriate solutions are highly demand. Herein, a programmatic treatment strategy is proposed for the development of a smart molecular prodrug (), which comprise a two-photon photosensitizer and a hypoxia-activated chemotherapeutic prodrug. A rhodamine dye was designed to connect them and track the drug release by the fluorescent signal generated through azo bond cleavage. The prodrug () can stay on the cell membrane and enrich at the tumor site. Upon light irradiation, the therapeutic effect was enhanced by a stepwise treatment: (i) direct generation of O on the cell membrane induced membrane destruction and promoted the uptake; (ii) deep tumor hypoxia caused by two-photon PDT process further triggered the activation of the chemotherapy prodrug. Both and experiments, have exhabited excellent tumor treatment effect. The innovative treatment strategy provides new strategy for the design of follow-up anticancer drugs.
Topics: Animals; Azo Compounds; Cell Membrane; Female; Fluorescent Dyes; HeLa Cells; Humans; Hypoxia; Mammary Neoplasms, Experimental; Photochemotherapy; Photons; Photosensitizing Agents; Prodrugs; Rhodamines; Singlet Oxygen; Staining and Labeling
PubMed: 33537100
DOI: 10.7150/thno.55014 -
Chemical Society Reviews Jun 2024Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with... (Review)
Review
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (, burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (, polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, ), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Topics: Prodrugs; Polymerization; Drug Carriers; Humans; Polymers; Nanoparticles; Drug Liberation; Free Radicals
PubMed: 38775004
DOI: 10.1039/d2cs01060g -
International Journal of Molecular... Dec 2022Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a...
Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.
Topics: Humans; Mice; Animals; Female; Prodrugs; Breast Neoplasms; Reactive Oxygen Species; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Cell Line, Tumor
PubMed: 36555298
DOI: 10.3390/ijms232415656 -
British Journal of Cancer Dec 1999The anti-tumour effects and mechanism of action of combretastatin A-4 and its prodrug, combretastatin A-4 disodium phosphate, were examined in subcutaneous and...
The anti-tumour effects and mechanism of action of combretastatin A-4 and its prodrug, combretastatin A-4 disodium phosphate, were examined in subcutaneous and orthotopically transplanted experimental colon tumour models. Additionally, the ability of these compounds to directly interfere with endothelial cell behaviour was also examined in HUVEC cultures. Combretastatin A-4 (150 mg kg(-1), intraperitoneally (i.p.)) and its water-soluble prodrug (100 mg kg(-1), i.p.) caused almost complete vascular shutdown (at 4 h), extensive haemorrhagic necrosis which started at 1 h after treatment and significant tumour growth delay in MAC 15A subcutaneous (s.c.) colon tumours. Similar vascular effects were obtained in MAC 15 orthotopic tumours and SW620 human colon tumour xenografts treated with the prodrug. More importantly, in the orthotopic models, necrosis was seen in vascularized metastatic deposits but not in avascular secondary deposits. The possible mechanism giving rise to these effects was examined in HUVEC cells. Here cellular networks formed in type I calf-skin collagen layers and these networks were completely disrupted when incubated with a non-cytotoxic concentration of combretastatin A-4 or its prodrug. This effect started at 4 h and was complete by 24 h. The same non-cytotoxic concentrations resulted in disorganization of F-actin and beta-tubulin at 1 h after treatment. In conclusion, combretastatin A-4 and its prodrug caused extensive necrosis in MAC 15A s.c. and orthotopic colon cancer and metastases, resulting in anti-tumour effects. Necrosis was not seen in avascular tumour nodules, suggesting a vascular mechanism of action.
Topics: Animals; Cell Division; Cells, Cultured; Collagen; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Neoplasms, Experimental; Neovascularization, Pathologic; Prodrugs; Stilbenes
PubMed: 10604728
DOI: 10.1038/sj.bjc.6692174