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1. A Comprehensive Review of Microneedles: Types, Materials, Processes, Characterizations and Applications

   https://doi.org/10.3390/polym13162815  

   Aldawood, Faisal Khaled; Andar, Abhay; Desai, Salil (August 2021, Polymers)

   null (Ed.)

   Drug delivery through the skin offers many advantages such as avoidance of hepatic first-pass metabolism, maintenance of steady plasma concentration, safety, and compliance over oral or parenteral pathways. However, the biggest challenge for transdermal delivery is that only a limited number of potent drugs with ideal physicochemical properties can passively diffuse and intercellularly permeate through skin barriers and achieve therapeutic concentration by this route. Significant efforts have been made toward the development of approaches to enhance transdermal permeation of the drugs. Among them, microneedles represent one of the microscale physical enhancement methods that greatly expand the spectrum of drugs for transdermal and intradermal delivery. Microneedles typically measure 0.1–1 mm in length. In this review, microneedle materials, fabrication routes, characterization techniques, and applications for transdermal delivery are discussed. A variety of materials such as silicon, stainless steel, and polymers have been used to fabricate solid, coated, hollow, or dissolvable microneedles. Their implications for transdermal drug delivery have been discussed extensively. However, there remain challenges with sustained delivery, efficacy, cost-effective fabrication, and large-scale manufacturing. This review discusses different modes of characterization and the gaps in manufacturing technologies associated with microneedles. This review also discusses their potential impact on drug delivery, vaccine delivery, disease diagnostic, and cosmetics applications. 

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2. Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

   https://doi.org/10.1002/adtp.201900107  

   Xi, Jingchao; Liu, Haipeng (December 2019, Advanced Therapeutics)

   Abstract Amphiphilic drugs are molecular drugs or drug conjugates possessing both hydrophilic and lipophilic properties. Representative amphiphilic drugs are composed of a pharmaceutical payload, a linker, and an appropriate amphiphilic modification. The physicochemical properties of amphiphilic drugs can be tailored by structure‐based engineering, which ultimately determine the drug molecules’ self‐assemble ability, bioavailability, protein binding, membrane anchoring, organ and intracellular distributions, side effects, and biological efficacy. Unlike the traditional carrier‐assistant drug delivery system, many of the amphiphilic drugs are carrier‐free and can self‐deliver to target sites/cells and access intracellular organelles without an external delivery carrier. This is achieved by molecular designs that control the delivery pathways of amphiphilic drugs at organ/tissue, cellular, and intracellular levels. In this review the recent advances in self‐delivery amphiphilic drugs and vaccines are highlighted, with emphasis on the underlying design principles and emerging applications. 

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3. Cytochrome c: Using Biological Insight toward Engineering an Optimized Anticancer Biodrug

   https://doi.org/10.3390/inorganics9110083  

   Delinois, Louis J.; De León-Vélez, Omar; Vázquez-Medina, Adriana; Vélez-Cabrera, Alondra; Marrero-Sánchez, Amanda; Nieves-Escobar, Christopher; Alfonso-Cano, Daniela; Caraballo-Rodríguez, Delvin; Rodriguez-Ortiz, Jael; Acosta-Mercado, Jemily; et al (November 2021, Inorganics)

   The heme protein cytochrome c (Cyt c) plays pivotal roles in cellular life and death processes. In the respiratory chain of mitochondria, it serves as an electron transfer protein, contributing to the proliferation of healthy cells. In the cell cytoplasm, it activates intrinsic apoptosis to terminate damaged cells. Insight into these mechanisms and the associated physicochemical properties and biomolecular interactions of Cyt c informs on the anticancer therapeutic potential of the protein, especially in its ability to subvert the current limitations of small molecule-based chemotherapy. In this review, we explore the development of Cyt c as an anticancer drug by identifying cancer types that would be receptive to the cytotoxicity of the protein and factors that can be finetuned to enhance its apoptotic potency. To this end, some information is obtained by characterizing known drugs that operate, in part, by triggering Cyt c induced apoptosis. The application of different smart drug delivery systems is surveyed to highlight important features for maintaining Cyt c stability and activity and improving its specificity for cancer cells and high drug payload release while recognizing the continuing limitations. This work serves to elucidate on the optimization of the strategies to translate Cyt c to the clinical market. 

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4. A multiscale coarse-grained model to predict the molecular architecture and drug transport properties of modified chitosan hydrogels

   https://doi.org/10.1039/d0sm01243b  

   Singhal, Ankush; Schneible, John D.; Lilova, Radina L.; Hall, Carol K.; Menegatti, Stefano; Grafmüller, Andrea (December 2020, Soft Matter)

   null (Ed.)

   Hydrogels constructed with functionalized polysaccharides are of interest in a multitude of applications, chiefly the design of therapeutic and regenerative formulations. Tailoring the chemical modification of polysaccharide-based hydrogels to achieve specific drug release properties involves the optimization of many tunable parameters, including (i) the type, degree ( χ ), and pattern of the functional groups, (ii) the water–polymer ratio, and (iii) the drug payload. To guide the design of modified polysaccharide hydrogels for drug release, we have developed a computational toolbox that predicts the structure and physicochemical properties of acylated chitosan chains, and their impact on the transport of drug molecules. Herein, we present a multiscale coarse-grained model to investigate the structure of networks of chitosan chains modified with acetyl, butanoyl, or heptanoyl moieties, as well as the diffusion of drugs doxorubicin (Dox) and gemcitabine (Gem) through the resulting networks. The model predicts the formation of different network structures, in particular the hydrophobically-driven transition from a uniform to a cluster/channel morphology and the formation of fibers of chitin chains. The model also describes the impact of structural and physicochemical properties on drug transport, which was confirmed experimentally by measuring Dox and Gem diffusion through an ensemble of modified chitosan hydrogels. 

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5. CardioGenAI: a machine learning-based framework for re-engineering drugs for reduced hERG liability

   https://doi.org/10.1186/s13321-025-00976-8  

   Kyro, Gregory W; Martin, Matthew T; Watt, Eric D; Batista, Victor S (December 2025, Journal of Cheminformatics)

   Abstract The link between in vitro hERG ion channel inhibition and subsequent in vivo QT interval prolongation, a critical risk factor for the development of arrythmias such as Torsade de Pointes, is so well established that in vitro hERG activity alone is often sufficient to end the development of an otherwise promising drug candidate. It is therefore of tremendous interest to develop advanced methods for identifying hERG-active compounds in the early stages of drug development, as well as for proposing redesigned compounds with reduced hERG liability and preserved primary pharmacology. In this work, we present CardioGenAI, a machine learning-based framework for re-engineering both developmental and commercially available drugs for reduced hERG activity while preserving their pharmacological activity. The framework incorporates novel state-of-the-art discriminative models for predicting hERG channel activity, as well as activity against the voltage-gated Na_V1.5 and Ca_V1.2 channels due to their potential implications in modulating the arrhythmogenic potential induced by hERG channel blockade. We applied the complete framework to pimozide, an FDA-approved antipsychotic agent that demonstrates high affinity to the hERG channel, and generated 100 refined candidates. Remarkably, among the candidates is fluspirilene, a compound which is of the same class of drugs as pimozide (diphenylmethanes) and therefore has similar pharmacological activity, yet exhibits over 700-fold weaker binding to hERG. Furthermore, we demonstrated the framework's ability to optimize hERG, Na_V1.5 and Ca_V1.2 profiles of multiple FDA-approved compounds while maintaining the physicochemical nature of the original drugs. We envision that this method can effectively be applied to developmental compounds exhibiting hERG liabilities to provide a means of rescuing drug development programs that have stalled due to hERG-related safety concerns. Additionally, the discriminative models can also serve independently as effective components of virtual screening pipelines. We have made all of our software open-source athttps://github.com/gregory-kyro/CardioGenAIto facilitate integration of the CardioGenAI framework for molecular hypothesis generation into drug discovery workflows. Scientific contribution This work introduces CardioGenAI, an open-source machine learning-based framework designed to re-engineer drugs for reduced hERG liability while preserving their pharmacological activity. The complete CardioGenAI framework can be applied to developmental compounds exhibiting hERG liabilities to provide a means of rescuing drug discovery programs facing hERG-related challenges. In addition, the framework incorporates novel state-of-the-art discriminative models for predicting hERG, Na_V1.5 and Ca_V1.2 channel activity, which can function independently as effective components of virtual screening pipelines. 

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