Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

Hornberger K.R., Araujo E.M.

Jadhav S.B., Amore B.M., Bockbrader H., Crass R.L., Chapel S., Sasiela W.J., Emery M.G.

AbstractPopulation pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70–100 kg) and high (> 100 kg vs. 70–100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.

Amore B.M., Cramer C., MacDougall D., Emery M.G.

Schjesvold F.H., Bakker N.A., Sonneveld P.

Blanco M., Gardinier K.M., Namchuk M.N.

Drug discovery and development has experienced an incredible paradigm shift in the past two decades. What once was considered a predominant R&D landscape of small molecules within a prescribed properties and mechanism space now includes an innovative wave of new chemical modalities. Scientists in the pharmaceutical industry can now strategize across a variety of modalities to find the best option to modulate a given target and provide treatment for a specific disease. We have witnessed a remarkable change not only in molecular design but also in creative approaches to drug delivery that have enabled advancement of novel modalities to clinical studies. In this Microperspective, we evaluate the critical differences between traditional small molecules and beyond rule of 5 compounds, peptides, oligonucleotides, and biologics for advancing into development, particularly their pharmacokinetic profiles and drug delivery strategies.

Tyler T., Schultz A., Venturini A., Giuliano C., Bernareggi A., Spezia R., Voisin D., Stella V.

Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK1 RA]) and palonosetron (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1 RA water solubility, preventing the occurrence of hypersensitivity and infusion-site reactions associated with these products. In this phase 1 study, subjects received a 30-minute placebo or fosnetupitant (17.6-353 mg) infusion and an oral NEPA or placebo capsule, with 2-sequence crossover treatment for fosnetupitant 118- to 353-mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300-mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler-identified infusion-site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment-related AEs did not increase with ascending fosnetupitant doses. The most common treatment-related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235-mg dose was equivalent, in terms of netupitant exposure, to 300-mg oral netupitant. The safety profile of a single fosnetupitant 235-mg infusion was similar to that of single-dose oral NEPA.

Bernhard S., Kaiser M., Burri C., Mäser P.

After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 µM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030.

A. M. Subbaiah M., Subramani L., Ramar T., Desai S., Sinha S., Mandlekar S., Kadow J.F., Jenkins S., Krystal M., Subramanian M., Sridhar S., Padmanabhan S., Bhutani P., Arla R., Meanwell N.A.

Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (1), designed to enhance the systemic drug delivery, were examined. Compared to previously reported prodrugs, optimized candidates delivered significantly enhanced plasma exposure and trough concentration (Cmin at 24 h) of 1 in rats while revealing differentiated PK paradigms based on the kinetics of prodrug activation and drug release. Prodrugs incorporating primary amine-containing amino acid promoieties offered the benefit of rapid bioactivation that translated into low circulating levels of the prodrug while delivering a high Cmax value of 1. Interestingly, the kinetic profile of prodrug cleavage could be tailored for slower activation by structural modification of the amino terminus to either a tertiary amine or a dipeptide motif, which conferred a circulating depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced Cmax and a further enhanced Cmin.

Pal A., Gori S., Yoo S., Thomas A.G., Wu Y., Friedman J., Tenora L., Bhasin H., Alt J., Haughey N., Slusher B.S., Rais R.

Extracellular vesicles (EVs) can carry pathological cargo and play an active role in disease progression. Neutral sphingomyelinase-2 (nSMase2) is a critical regulator of EV biogenesis, and its inhibition has shown protective effects in multiple disease states. 2,6-Dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)phenol (DPTIP) is one of the most potent (IC50 = 30 nM) inhibitors of nSMase2 discovered to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), limiting its clinical development. To overcome DPTIP's PK limitations, we synthesized a series of prodrugs by masking its phenolic hydroxyl group. When administered orally, the best prodrug (P18) with a 2',6'-diethyl-1,4'-bipiperidinyl promoiety exhibited >fourfold higher plasma (AUC0-t = 1047 pmol·h/mL) and brain exposures (AUC0-t = 247 pmol·h/g) versus DPTIP and a significant enhancement of DPTIP half-life (2 h vs ∼0.5 h). In a mouse model of acute brain injury, DPTIP released from P18 significantly inhibited IL-1β-induced EV release into plasma and attenuated nSMase2 activity. These studies report the discovery of a DPTIP prodrug with potential for clinical translation.

Ayre J., Redmond J.M., Vitulli G., Tomlinson L., Weaver R., Comeo E., Bosquillon C., Stocks M.J.

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing.

Sun D., Gao W., Hu H., Zhou S.

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

Miller B.S., Yuen K.C.

Markovic M., Zur M., Garsiani S., Porat D., Cvijić S., Amidon G.L., Dahan A.

The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.

Braeckman R., Guenther S., Mickle T.C., Barrett A.C., Smith A., Oh C.

Objective: 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. Methods: 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. Results: 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 (Cmax) were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC0-last) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized Cmax, AUC0-last, and AUC0-inf for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that Cmax and AUC0-inf 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. Conclusion: The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional Cmax and AUC0-inf 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.

Chen S., Gao Y., Lou X., Henry R.F., Stolarik D.F., Lipert M.P., Sheikh A.Y., Zhang G.G.

Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pKa = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 μg/mL at pH 1-6.8, dose number of 1.31 × 104), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

Imai T., Isasaka M., Oyama Y., Takagi Y., Ohura K., Kotani S., Nakada Y.

de Souza M.M., Gini A.L., Moura J.A., Scarim C.B., Chin C.M., dos Santos J.L.

Absorption and permeability are critical physicochemical parameters that must be balanced to achieve optimal drug uptake. These key factors are closely linked to the maximum absorbable dose required to provide appropriate plasma levels of drugs. Among the various strategies employed to enhance drug solubility and permeability, prodrug design stands out as a highly effective and versatile approach for improving physicochemical properties and enabling the optimization of biopharmaceutical and pharmacokinetic parameters while mitigating adverse effects. Prodrugs are compounds with reduced or no activity that, through bio-reversible chemical or enzymatic processes, release an active parental drug. The application of this technology has led to significant advancements in drug optimization during the design phase, and it offers broad potential for further development. Notably, approximately 13% of the drugs approved by the U.S. Food and Drug Administration (FDA) between 2012 and 2022 were prodrugs. In this review article, we will explore the application of prodrug strategies to enhance permeability, describing examples of market drugs. We also describe the use of the prodrug approach to optimize PROteolysis TArgeting Chimeras (PROTACs) permeability by using conjugation technologies. We will highlight some new technologies in prodrugs to enrich permeability properties, contributing to developing new effective and safe prodrugs.

von Glasenapp V., C. Almeida A., Chang D., Gasic I., Winssinger N., Gotta M.

Abstract The ability to control the activity of kinases spatially and temporally is essential to elucidate the role of signalling pathways in development and physiology. Progress in this direction has been hampered by the lack of tools to manipulate kinase activity in a highly controlled manner in vivo. Here we report a strategy to modify BI2536, the well characterized inhibitor of the conserved and essential mitotic kinase Polo-like kinase 1 (Plk1). We introduce the same coumarin photolabile protecting group (PPG) at two positions of the inhibitor. At one position, the coumarin prevents the interaction with Plk1, at the second it masks an added carboxylic acid, important for cellular retention. Exposure to light results in removal of both PPGs, leading to the activation of the inhibitor and its trapping inside cells. We demonstrate the efficacy of the caged inhibitor in three-dimensional spheroid cultures: by uncaging it with a single light pulse, we can inhibit Plk1 and arrest cell division, a highly dynamic process, with spatio-temporal control. Our design can be applied to other small molecules, providing a solution to control their activity in living cells with unprecedented precision.

Li H., Shen X., Chu Y., Yuan P., Shuai Q.

Zhu J., Jia X., Ren S., Zhang Z., Li H., Wang J., Song B., Wu W., Peng C.

ABSTRACTSince the eradication of smallpox, zoonotic poxviruses, such as the mpox virus (MPXV), continue to pose a threat to public health. Identifying drugs that reduce poxvirus infection and replication, as well as understanding their molecular mechanisms, is essential for epidemic control. Polo‐like kinase 1 (PLK1) has been shown to facilitate vaccinia virus (VACV) infection and replication. This study confirms the effects of the PLK1 inhibitors HMN‐214 and ON‐01910 on VACV replication in A549 cells. Both viral titers and DNA loads were significantly reduced in treated cells after infection. Additionally, ON‐01910 demonstrated broad‐spectrum antiviral activity against the lumpy skin disease virus (LSDV) and the infectious bovine rhinotracheitis virus (IBRV) in vitro. PLK1 knockdown in A549 cells also led to a reduction in VACV protein expression, viral titers, and DNA levels. Further analysis showed that VACV infection leads to the accumulation of PLK1 near viral factories. However, despite its strong in vitro effects, ON‐01910 did not significantly reduce VACV replication in mice. These findings highlight the critical role of PLK1 in VACV replication and its potential as a target for antiviral therapy against orthopoxviruses.

Faisal A.F., Mustafa Y.F.

ABSTRACTDue to its biodiversity, traditional medicine has been recognized worldwide for centuries and continues to affect the development of complementary and alternative therapies. A wide variety of spices, herbs, and trees are known for their curative effects. Chili pepper (Ch‐p), a spice‐utilizing fruit, is rich in natural medicinally bioactive compounds, such as flavonoids, capsaicinoids, and many other phytochemicals and phytonutrients. Operating in synergy and consortium, these compounds demonstrate their functionality, in comparison to lonely treatment, as active agents in handling many disorders. These may include abnormal coagulation, oxidative stress, obesity, diabetes, inflammation, cancer, and microbe‐inducing diseases. Recently, capsaicinoids, particularly capsaicin, have been shown to manage the symptoms of significant viral diseases, including COVID‐19. Capsaicin also has the potential to be an effective anesthetic agent and enables Ch‐p to be expandedly employed as a topical preparation in relieving pain as well. The phytochemicals of Ch‐p are not only beneficial and inexpensive phyto‐alternatives in disease management, but they can also be used as scaffolds for the production of novel medicines. The study also substantiates the role of the TRPV1 receptor in the mitigation of chronic diseases in conjunction with capsaicin. Nevertheless, the consumption of Ch‐p is the subject of limited medicinal research, necessitating the confirmation of the results from animal studies. The nutritional and biomedical prospection of Ch‐p‐derived products has been addressed in an accessible format in this artifact, with the potential to precisely enhance and enrich our pharmaceutical industries in the pursuit of human well‐being.

Kurian R., Wang H.

A prodrug is a molecule that lacks pharmacological activity, but upon enzymatic bioactivation, it can generate a therapeutically active molecule. The primary reason behind the design of a prodrug is to help circumvent challenges associated with the physicochemical properties of a drug molecule, such as solubility, absorption, distribution, and instability. Chemotherapy has been at the forefront of cancer treatment for over 70 years due to its ability to target rapidly proliferating tumor cells. However, a major concern with conventional chemotherapy is the lack of selectivity and its associated side toxicity, which can severely impact patients’ quality of life. In oncology, prodrugs have been explored to enhance the bioavailability, improve efficacy, and minimize systemic toxicity of chemotherapeutic agents. Prodrugs activated by enzymes unique to a tumor microenvironment can significantly increase targeted delivery of chemotherapeutic drugs. This review aims to highlight commonly used chemotherapeutic prodrugs, including both alkylating and non-alkylating agents, and discuss their clinical relevance, mechanisms of bioactivation, and toxicity concerns.

Jacob S., Kather F.S., Boddu S.H., Attimarad M., Nair A.B.

Nanosuspensions (NS), with their submicron particle sizes and unique physicochemical properties, provide a versatile solution for enhancing the administration of medications that are not highly soluble in water or lipids. This review highlights recent advancements, future prospects, and challenges in NS-based drug delivery, particularly for oral, ocular, transdermal, pulmonary, and parenteral routes. The conversion of oral NS into powders, pellets, granules, tablets, and capsules, and their incorporation into film dosage forms to address stability concerns is thoroughly reviewed. This article summarizes key stabilizers, polymers, surfactants, and excipients used in NS formulations, along with ongoing clinical trials and recent patents. Furthermore, a comprehensive analysis of various methods for NS preparation is provided. This article also explores various in vitro and in vivo characterization techniques, as well as scale-down technologies and bottom-up methods for NS preparation. Selected examples of commercial NS drug products are discussed. Rapid advances in the field of NS could resolve issues related to permeability-limited absorption and hepatic first-pass metabolism, offering promise for medications based on proteins and peptides. The evolution of novel stabilizers is essential to overcome the current limitations in NS formulations, enhancing their stability, bioavailability, targeting ability, and safety profile, which ultimately accelerates their clinical application and commercialization.

Berrino E., Thibaudeau S.

Urbaniak T., Milasheuski Y., Musiał W.

To reduce the risk of side effects and enhance therapeutic efficiency, drug delivery systems that offer precise control over active ingredient release while minimizing burst effects are considered advantageous. In this study, a novel approach for the controlled release of lamivudine (LV) was explored through the fabrication of polyelectrolyte-coated microparticles. LV was covalently attached to poly(ε-caprolactone) via ring-opening polymerization, resulting in a macromolecular prodrug (LV-PCL) with a hydrolytic release mechanism. The LV-PCL particles were subsequently coated using the layer-by-layer (LbL) technique, with polyelectrolyte multilayers assembled to potentially modify the carrier’s properties. The LbL assembly process was comprehensively analyzed, including assessments of shell thickness, changes in ζ-potential, and thermodynamic properties, to provide insights into the multilayer structure and interactions. The sustained LV release over 7 weeks was observed, following zero-order kinetics (R2 > 0.99), indicating a controlled and predictable release mechanism. Carriers coated with polyethylene imine/heparin and chitosan/heparin tetralayers exhibited a distinct increase in the release rate after 6 weeks and 10 weeks, respectively, suggesting that this coating can facilitate the autocatalytic degradation of the polyester microparticles. These findings indicate the potential of this system for long-term, localized drug delivery applications, requiring sustained release with minimal burst effects.

Salve K.S., Bhatia N.M., Nadaf S.J.

Lozano Baró E., Catti F., Estarellas C., Ghashghaei O., Lavilla R.

Xu W., Jia A., Lei Z., Wang J., Jiang H., Wang S., Wang Q.

Self-immolative prodrugs have gained significant attention as an innovative approach for targeted cancer therapy. These prodrugs are engineered to release the active anticancer agents in response to specific triggers within the tumor microenvironment, thereby improving therapeutic precision while reducing systemic toxicity. This review focuses on the molecular architecture and design principles of self-immolative prodrugs, emphasizing the role of stimuli-responsive linkers and activation mechanisms that enable controlled drug release. Recent advancements in this field include the development of prodrugs that incorporate targeting moieties for enhanced site-specificity. Moreover, the review discusses the incorporation of targeting moieties to achieve site-specific drug delivery, thereby improving the selectivity of treatment. By summarizing key research from the past five years, this review highlights the potential of self-immolative prodrugs to revolutionize cancer treatment strategies and pave the way for their integration into clinical practice.

Barati V., Hruzíková A., Procházková E., Zavřel M., Kozák J., Trylčová J., Rejman D., Weber J., Bogdanová K., Kolář M., Baszczyňski O.

Mashweu A.R., Azov V.A.

The bioavailability, release, and stability of pharmaceuticals under physicochemical conditions is the major cause of drug candidates failing during their clinical trials. Therefore, extensive efforts have been invested in the development of novel drug delivery systems that are able to transport drugs to a desired site and improve bioavailability. Hydrogels, and peptide hydrogels in particular, have been extensively investigated due to their excellent biocompatibility and biodegradability properties. However, peptide hydrogels often have weak mechanical strength, which limits their therapeutic efficacy. Therefore, a number of methods for improving their rheological properties have been established. This review will cover the broad area of drug delivery, focusing on the recent developments in this research field. We will discuss the variety of different types of nanocarrier drug delivery systems and then, more specifically, the significance and perspectives of peptide-based hydrogels. In particular, the interplay of intermolecular forces that govern the self-assembly of peptide hydrogels, progress made in understanding the distinct morphologies of hydrogels, and applications of non-canonical amino acids in hydrogel design will be discussed in more detail.