Exploring Ester Prodrugs: A Comprehensive Review of Approaches, Applications, and Methods

The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.

pH-sensitive Nanoparticles for High Loading and Efficient Delivery of Doxorubicin

An acid-sensitive delivery system based on acylhydrazone bond was developed for high loading and efficient delivery of doxorubicin.Doxorubicin(DOX)was covalently combined with dihydrazide adipate to form acid-sensitive hydrazone bond based on Schiff base reaction,then the intermediate was covalently combined with carboxymethyl chitosan through amide bond to form polymeric prodrugs,and nanoparticles were formed through self-assembling.Moreover,the structural and particle properties of CMCS-ADH-DOX were characterized by ultraviolet visible near infrared spectrophotometry(UV),nuclear magnetic resonance spectroscopy(^(1)H-NMR),fourier transform infrared spectroscopy(FT-IR),dynamic light scattering(DLS),and transmission electron microscopy(TEM).The mean diameter of the self-assembled nanoparticles is 165 nm,while the morphology is a relatively uniform spherical shape.Moreover,these DOXloaded nanoparticles showed pH-triggered drug release behavior.Compared with free DOX,CAD NPs showed lower toxic side effects in L929 cells and similar toxicity in 4T1 cells.The experimental results indicate that the CMCS-ADH-DOX nanoparticles may be used as an acid-sensitive targeted delivery system with good application prospect for cancer.

Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy

Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

Triclosan-conjugated,Lipase-responsive Polymeric Micelles for Eradication of Staphylococcal Biofilms

Bacterial biofilms present a significant challenge in treating drug-resistant infections,necessitating the development of innovative nanomedicines.In this study,we introduce triclosan-conjugated,lipase-responsive polymeric micelles designed to exploit biofilm properties and serve as a responsive drug delivery platform.The micelles were created using an amphiphilic block polymer synthesized via ring-opening polymerization ofε-caprolactone(CL)and triclosan-containing cyclic trimethylene carbonate(MTC-Tri).Poly(ethylene glycol)(PEG-OH)acted as the macro-initiator,resulting in micelles with a PEG shell that facilitated their penetration into bacterial biofilms.An important advantage of our micelles lies in their interaction with local bacterial lipases within biofilms.These lipases triggered rapid micelle degradation,releasing triclosan in a controlled manner.This liberated triclosan effectively eliminated bacteria embedded in the biofilms.Notably,the triclosan-conjugated micelles displayed minimal toxicity to murine fibroblasts,indicating their biocompatibility and safety.This finding emphasizes the potential application of these micelles in combatting drug resistance observed in bacterial biofilms.Our triclosan-conjugated,lipase-responsive polymeric micelles exhibit promising characteristics for addressing drug resistance in bacterial biofilms.By harnessing biofilm properties and implementing a responsive drug delivery system,we seek to provide an effective solution in the fight against drug-resistant bacteria.

GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

A ROS-Responsive Aspirin Polymeric Prodrug for Modulation of Tumor Microenvironment and Cancer Immunotherapy

Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.

A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma

Melanoma,as the most aggressive and treatment-resistant skin malignancy,is responsible for about 80%of all skin cancer mortalities.Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate.Therefore,early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical.In this study,a sulfur dioxide(SO_(2))polymer prodrug was designed as both an intracellular glutathione(GSH)-responsive SO_(2) generator and a carrier of doxorubicin(DOX),and used for the treatment of subcutaneous and metastatic melanoma.Firstly,chemical conjugation of 4-N-(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid(DIBA)onto the side chains of methoxy poly(ethylene glycol)grafted dextran(mPEG-g-Dex)resulted in the synthesis of the amphiphilic polymer prodrug of SO_(2),mPEG-g-Dex(DIBA).The obtained mPEG-g-Dex(DIBA)could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO_(2) release behavior.Subsequently,DOX was encapsulated into the core of mPEG-g-Dex(DIBA)micelles to form DOX-loaded nanoparticles(PDDN-DOX).The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO_(2) into the tumor cells.As a result,PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO_(2) and toxic effects of DOX.Furthermore,in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma.Collectively,our present work demonstrates that the combination of SO_(2)-based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases.

Polymeric prodrug for bio-controllable gene and drug co-delivery

A polymeric polyethylenimine(PEI)-based prodrug of anticancer doxorubicin(DOX)(PEI-hyd-DOX) was designed by attaching DOX to PEI via an acid-labile hydrazone bond, for the achievement of biocontrollable gene and drug co-delivery in response to the intracellular acid microenvironments in the late endosome/lysosome compartments. The cytotoxicity of PEI-hyd-DOX was evaluated by the MTT assay and the cellular uptake was monitored using confocal laser scanning microscopy. The polymeric prodrug can respond with a high sensitivity to the specific acid condition inside cells, thus permitting the precise biocontrol over intracellular drug liberation with high drug efficacy. The chemical attachment of drug molecules also led to the relatively reduced toxicity and the enhanced transfection efficiency compared with parent PEI. The resulting data adumbrated the potential of PEI-hyd-DOX to co-deliver DOX and therapeutic gene for the combination of chemotherapy and gene therapy.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases.Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment.However,only a limited number of nanotherapies have enter clinical trials or are clinically approved.Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system(MPS),resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors.Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy.Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages.Polymer conjugation revived the parent camptothecin agent(e.g.,7-ethyl-10-hydroxy-camptothecin),enabling lipid nanoparticle encapsulation.Furthermore,macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin,increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy.When tested in a preclinical murine model of breast cancer,macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles.Furthermore,intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity.Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity.This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Monoclonal Antibody-conjugated Polyphosphoester-hyd-DOX Prodrug Nanoparticles for Targeted Chemotherapy of Liver Cancer Cells

In order to overcome the limitation of traditional active nano-therapeutic drugs on tumor targeting efficiency which cannot reach the receptor/target in sufficient amount in the body,in this work,we developed a monoclonal antibody(mAb)and a polymer-hyd-doxorubicin prodrug conjugate,which enables the self-assembled nanoparticles to have precise targeting,tumor tissue aggregation and pH-sensitive drug release.We first prepared an amphiphilic polymer prodrug,abbreviated as H2N-PEEP-b-PBYP-hyd-DOX,via a combination of ring-opening polymerization(ROP)and"click"chemistry,in which PEEP and PBYP represent two kinds of phosphoester segmemts,-hyd-is hydrazone bond.After self-assembly into prodrug nanoparticles(PDNPs)with a diameter of about 93 nm,CD147 mAb was conjugated onto the PDNPs by EDC/NHS chemistry to form mAb-PDNPs.For the PDNPs and mAb-PDNPs,we also investigated their stability,in vitro drug release behavior and cellular uptake.The results showed that the pH-responsive PDNPs can remain relatively stable under the condition of PB 7.4 buffer solution.However,under acidic conditions or in the presence of phosphodiesterase I(PDE I),both the amount and rate of DOX release increased at the same incubation period.Cytotoxicity assay showed that mAb-PDNPs exhibited higher cytotoxicity(IC50:1.12 mg·L^(-1))against HepG2 cells than PDNPs(IC50:2.62 mg·L^(-1))without monoclonal antibody.The nanoparticles with antibodies mAb-PDNPs have relatively better stability and can directly achieve the targeting drug delivery through CD147 mAb.