-
Biochemical Pharmacology Jul 2022Despite significant preclinical promise as anticancer agents, vascular-disrupting agents have yet to fulfil their clinical potential due to systemic toxicities. ICT2588...
Despite significant preclinical promise as anticancer agents, vascular-disrupting agents have yet to fulfil their clinical potential due to systemic toxicities. ICT2588 is a tumour-selective MT1-MMP-targeted prodrug of azademethylcolchicine, ICT2552. We investigate activation of ICT2588 and subsequent release of ICT2552 in tumour cells, and examine its ability to induce G2/M cell cycle arrest. We also explore synergism between ICT2588 and ATR inhibition, since colchicine, in addition to its vascular-disrupting properties, is known to induce G2/M arrest, DNA damage, and trigger apoptosis. Several ATR inhibitors are currently undergoing clinical evaluation. The cellular activation of ICT2588 was observed to correlate with MT1-MMP expression, with selective release of ICT2552 not compromised by cellular uptake and prodrug activation mechanisms. ICT2588 induced G2/M arrest, and triggered apoptosis in MT1-MMP-expressing cells, but not in cells lacking MT1-MMP expression, while ICT2552 itself induced G2/M arrest and triggered apoptosis in both cell lines. Interestingly, we uncovered that the intracellular release and accumulation dynamics of ICT2552 subsequent to prodrug activation provided synergism with an ATR inhibitor in a way not observed with direct administration of ICT2552. These findings have important potential implications for clinical combinations of ICT2588 and DNA repair inhibitors.
Topics: Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Colchicine; G2 Phase Cell Cycle Checkpoints; Matrix Metalloproteinase 14; Neoplasms; Prodrugs; Protein Kinase Inhibitors
PubMed: 35598808
DOI: 10.1016/j.bcp.2022.115095 -
Journal of Nanobiotechnology Jan 2024Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated...
BACKGROUND
Off-targeted distribution of chemotherapeutic drugs causes severe side effects, further leading to poor prognosis and patient compliance. Ligand/receptor-mediated targeted drug delivery can improve drug accumulation in the tumor but it always attenuated by protein corona barriers.
RESULTS
To address these problems, a radically different strategy is proposed that can leave the off-targeted drugs inactive but activate the tumor-distributed drugs for cancer-targeting therapy in a tumor microenvironment-independent manner. The feasibility and effectiveness of this strategy is demonstrated by developing an ultrasound (US)-activated prodrug-loaded liposome (CPBSN38L) comprising the sonosensitizer chlorin e6 (Ce6)-modified lipids and the prodrug of pinacol boronic ester-conjugated SN38 (PBSN38). Once CPBSN38L is accumulated in the tumor and internalized into the cancer cells, under US irradiation, the sonosensitizer Ce6 rapidly induces extensive production of intracellular reactive oxygen species (ROS), thereby initiating a cascade amplified ROS-responsive activation of PBSN38 to release the active SN38 for inducing cell apoptosis. If some of the injected CPBSN38L is distributed into normal tissues, the inactive PBSN38 exerts no pharmacological activity on normal cells. CPBSN38L exhibited strong anticancer activity in multiple murine tumor models of colon adenocarcinoma and hepatocellular carcinoma with no chemotherapy-induced side effects, compared with the standard first-line anticancer drugs irinotecan and topotecan.
CONCLUSIONS
This study established a side-effect-evitable, universal, and feasible strategy for cancer-targeting therapy.
Topics: Humans; Animals; Mice; Liposomes; Prodrugs; Reactive Oxygen Species; Adenocarcinoma; Colonic Neoplasms; Antineoplastic Agents; Cell Line, Tumor; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Tumor Microenvironment
PubMed: 38169390
DOI: 10.1186/s12951-023-02195-5 -
Theranostics 2023Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an...
Chemoimmunotherapy is a promising approach in cancer immunotherapy. However, its therapeutic efficacy is restricted by high reactive oxygen species (ROS) levels, an abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) as well as immune checkpoints for escaping immunosurveillance. Herein, a new type of TME and reduction dual-responsive polymersomal prodrug (TRPP) nanoplatform was constructed when the D-peptide antagonist (PPA-1) of programmed death ligand-1 was conjugated onto the surface, and talabostat mesylate (Tab, a fibroblast activation protein inhibitor) was encapsulated in the watery core (PPA-TRPP/Tab). Doxorubicin (DOX) conjugation in the chain served as an immunogenic cell death (ICD) inducer and hydrophobic part. PPA-TRPP/Tab reassembled into a micellar structure with TME modulation by Tab, ROS consumption by 2, 2'-diselanediylbis(ethan-1-ol), immune checkpoint blockade by PPA-1 and ICD generation by DOX. This resolved the dilemma between a hydrophilic Tab release in the TME for CAF inhibition and intracellular hydrophobic DOX release for ICD via re-assembly in weakly acidic TME with polymersome-micelle transformation. results indicated that PPA-TRPP/Tab could improve tumor accumulation, suppress CAF formation, downregulate regulatory T cells and promote T lymphocyte infiltration. In mice, it gave a 60% complete tumor regression ratio and a long-term immune memory response. The study offers potential in tumor eradication via exploiting an "all-in-one" smart polymeric nanoplatform.
Topics: Animals; Mice; Prodrugs; Immune Checkpoint Inhibitors; Tumor Microenvironment; Reactive Oxygen Species; Immunogenic Cell Death; Antineoplastic Agents; Immunotherapy; Doxorubicin; Neoplasms; Micelles; Cell Line, Tumor
PubMed: 37064869
DOI: 10.7150/thno.83912 -
ChemMedChem Dec 2021The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In... (Review)
Review
The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the "mutual prodrug" approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Drug Synergism; Enzyme Inhibitors; Fluorouracil; Humans; Neoplasms; Prodrugs
PubMed: 34415107
DOI: 10.1002/cmdc.202100473 -
Cancer Letters Dec 2020We hypothesised that synthetic HDL nanoparticles carrying a gemcitabine prodrug and apolipoprotein A-II (sHDLGemA2) would target scavenger receptor-B1 (SR-B1) to...
We hypothesised that synthetic HDL nanoparticles carrying a gemcitabine prodrug and apolipoprotein A-II (sHDLGemA2) would target scavenger receptor-B1 (SR-B1) to preferentially and safely deliver gemcitabine into pancreatic ductal adenocarcinoma (PDAC). We designed, manufactured and characterised sHDLGemA2 nanoparticles sized ~130 nm, incorporating 20 mol% of a gemcitabine prodrug within the lipid bilayer, which strengthens on adding ApoA-II. We measured their ability to inhibit growth in cell lines and cell-derived and patient-derived murine PDAC xenografts. Fluorescent-labelled sHDLGemA2 delivered gemcitabine inside xenografts. Xenograft levels of active gemcitabine after sHDLGemA2 were similar to levels after high-dose free gemcitabine. Growth inhibition in mice receiving 4.5 mg gemcitabine/kg/d, carried in sHDLGemA2, was equivalent to inhibition after high-dose (75 mg/kg/d) free gemcitabine, and greater than inhibition after low-dose (4.5 mg/kg/d) free gemcitabine. sHDLGemA2 slowed growth in semi-resistant cells and a resistant human xenograft. sHDLGemA2 targeted xenografts more effectively than sHDLGemA1. SR-B1 was over-expressed in PDAC cells and xenografts. Targeting by ApoA-II was suppressed by anti-SR-B1. Because sHDLGemA2 provided only ~6% of the free gemcitabine dose for an equivalent response, patient side effects can be greatly reduced, and the sHDLGemA2 concept should be developed through clinical trials.
Topics: Animals; Apolipoprotein A-II; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Humans; Lipoproteins, HDL; Male; Mice; Nanoparticles; Pancreatic Neoplasms; Particle Size; Prodrugs; Scavenger Receptors, Class B; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 32949679
DOI: 10.1016/j.canlet.2020.08.045 -
Molecules (Basel, Switzerland) Dec 2021Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit In the late 1980s/early 1990s, TG was... (Review)
Review
Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50-100 nM TG is sustained for >24-48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC for killing of <100 nM. Conjugation of 12-ADT to a series of 5-8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.
Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Humans; Neoplasm Proteins; Neoplasms; Prodrugs; Thapsigargin
PubMed: 34946547
DOI: 10.3390/molecules26247469 -
Drug Design, Development and Therapy 2020Prodrug technology-based combination drug therapy has been exploited as a promising treatment strategy to achieve synergistic lung cancer therapy, reduce drug dose, and...
PURPOSE
Prodrug technology-based combination drug therapy has been exploited as a promising treatment strategy to achieve synergistic lung cancer therapy, reduce drug dose, and decrease side effects. In the present study, we synthesized a pH and glutathione (GSH) sensitive prodrug, cisplatin (CIS) and doxorubicin (DOX) conjugates (CIS-DOXp). CIS-DOXp was loaded by nanocarriers and delivered into the tumor site.
METHODS
pH and GSH sensitive CIS-DOX prodrug (CIS-DOXp) was synthesized by conjugating GSH responsive CIS prodrug with pH sensitive DOX prodrug. CIS-DOXp-loaded nanocarriers (CIS-DOXp NC) were prepared using emulsification and solvent evaporation method. The morphology, particle size, polydispersity index (PDI) and zeta potential of nanocarriers were measured. In vitro cytotoxicity of nanocarriers and the corresponding free drugs was examined using the MTT assay. In vivo anti-tumor efficiency and biodistribution behaviors were evaluated on lung cancer mice models.
RESULTS
The size, PDI, zeta potential, CIS loading efficiency, and DOX loading efficiency of CIS-DOXp NC were 128.6 ± 3.2 nm, 0.196 ± 0.021, 15.7 ± 1.7 mV, 92.1 ± 2.1%, and 90.4 ± 1.8%, respectively. The best cell killing ability (the lowest combination index of 0.57) was found at the combination ratio of 1:3 (CIS:DOX, w/w) in the drugs co-loaded formulations, indicating the strongest synergism effect. CIS-DOXp NC showed the best tumor inhibition efficiency (79.9%) in mice with negligible body weight lost.
CONCLUSION
CIS-DOXp NC could be applied as a promising system for the synergistic chemotherapy of lung cancer.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Female; Glutathione; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Structure; Nanoparticles; Neoplasms, Experimental; Particle Size; Prodrugs
PubMed: 33268983
DOI: 10.2147/DDDT.S260253 -
Journal of Child and Adolescent... Jun 2022The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new...
Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder.
The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations () were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized , AUC, and AUC for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that and AUC proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional and AUC across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.
Topics: Area Under Curve; Attention Deficit Disorder with Hyperactivity; Biological Availability; Central Nervous System Stimulants; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Humans; Methylphenidate; Prodrugs
PubMed: 35666231
DOI: 10.1089/cap.2022.0015 -
Journal of Cellular and Molecular... Aug 2022KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy...
KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER of 1.56-2.37 compared with AQ4N SER of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs.
Topics: Anthraquinones; Cell Hypoxia; Cell Line, Tumor; Humans; Hypoxia; Prodrugs; Triple Negative Breast Neoplasms
PubMed: 35841287
DOI: 10.1111/jcmm.17486 -
European Journal of Medicinal Chemistry Mar 2022Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the...
Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
Topics: Aminosalicylic Acid; Animals; Antitubercular Agents; Biological Availability; Mice; Prodrugs; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35219151
DOI: 10.1016/j.ejmech.2022.114201