Therapeutic Drug Delivery Research Articles

Neo-Glycolipid Oximes as Intestinal Permeation Enhancers for Peptide Hormone PYY3-36.

Herein, we describe the design and synthesis of 16 neo-glycolipids that are potential permeation enhancers for oral drug delivery of peptide therapeutics. These amphiphilic neo-glycolipids are composed of fatty acids and various carbohydrates (D-glucose, lactose, cellobiose, maltose) via an oxime linker. The ability of the synthesized neo-glycolipids to enhance permeation of fluorescein-labelled dextran (4 kDa) or 3H-mannitol across intestinal epithelium was investigated in vitro using monolayers of human epithelial Caco-2 cells. Their effects were compared with (pre-)clinically known enhancers as reference compounds; sodium salts of octanoic, decanoic, and dodecanoic acid, and sodium salcaprozate (SNAC). Most neo-glycolipids increased the permeation of the model compounds, proving that neo-glycolipids, which possess vastly different properties from the reference compounds, e.g., in terms of clogD and polar surface area, are effective permeation enhancers. The neo-glycolipid based on decanoic acid and glucose was more potent than related compounds based on disaccharides. Significant differences in solubility and cellular compatibility were found for neo-glyolipids based on different carbohydrates. Finally, neo-glycolipids were evaluated as permeation enhancers for the peptide hormone PYY3-36. Glucose- and maltose-derived neo-glycolipids based on decanoic and dodecanoic acid showed promising enhancements in PYY3-36 permeation while maintaining good cellular compatibility, relevant for oral delivery of obesity treatments.

Targeted isolation of extracellular vesicles from cell culture supernatant using immuno-affinity chromatography

Extracellular vesicles (EVs) have emerged as promising therapeutics with broad clinical applications as diagnostic biomarkers and therapeutic drug delivery systems. Yet, these biopharmaceuticals pose a challenge in terms of manufacturing due to their complexity and heterogeneity. Despite advancements in the field, current purification technologies lack scalability and/or selectivity. Affinity chromatography (AC) − coupling unmatched specificity and scalability − could be used to simplify purification processing and generate clinical-grade EVs with higher titers and purity.In the present work, we report the implementation of an immuno-AC resin to capture and purify EVs directly from clarified cellular feedstocks. Firstly, to guide and support marker selection, vesicle phenotype characterization was conducted using single particle interferometric reflectance image sensing (SP-IRIS) coupled with immunofluorescence. CD81 was the marker which shown to be more present and more likely to have the other markers (CD63 and CD9). Thus, anti-CD81 VHH ligand was generated and evaluated towards recombinant CD81 protein and CD81 bearing EV particles using surface plasmon resonance (SPR). Different chromatographic studies with Anti-CD81 ligand immobilized onto agarose beads resin were conducted to optimize the process parameters (residence time, dynamic binding capacity and impurity clearance). At residence time of 2 min, on average 40 % of pure triple tetraspanin-positive EV fraction was recovered. The enrichment in EV particles herein obtained, based on scale-up calculations, it would be possible to produce 1 × 1013 EVs from a 1L cell culture, while meeting impurity requirements in a single-step purification process (impurity removal over 2 log reduction value). A single-step purification process is possible, enabling the successful isolation of homogeneous EVs population, counting with a final HCP titer of 60 ng/mL and 9 ng/mL of dsDNA impurities. EV’s morphological integrity and internalization ability were also demonstrated, showcasing elution’s efficiency under mild conditions.Overall, this work contributes to the development of a novel, highly specific, AC technology using a camelid-derived affinity ligand which, bridging the scalability requirements demanded of large-scale production, could potentiate the advent of EV-based therapies.

Nano-formulations for the Management of Epilepsy: Synthetic and Herbal Drug Perspectives

Introduction: Epilepsy is a multifaceted neurological disorder impacting many individuals globally. Although the main treatment method is through medicines, many patients do not respond to existing drugs. This has spurred extensive research for new therapeutic targets and drug delivery methods. Inflammation and oxidative stress have been associated with the development and progression of epilepsy. Nanomedicine-based treatments focussing on these pathways could provide a promising way to enhance treatment results. Objective: This review aims to provide insights into enhancing antiepileptic therapy through the development of nanoformulations of synthetic and herbal drugs. Methods: A comprehensive review of existing literature was conducted to evaluate the potential of nanoformulations in improving the delivery and efficacy of antiepileptic drugs. The review covers the pathophysiological hypotheses of epilepsy, including the glutamatergic, GABAergic, oxidative stress, and neuroinflammation hypotheses, and examines the role of neurotransmitter imbalances in seizure activity. Results: Nanoformulations offer promising advantages for epilepsy treatment by enhancing drug delivery across the blood-brain barrier, reducing required dosages, and minimizing side effects. The utilization of nanoparticles can improve the bioavailability and targeting of AEDs, potentially leading to better seizure control. However, challenges such as ensuring biocompatibility and optimizing nanoparticle characteristics remain. Conclusion: While significant progress has been made in understanding epilepsy and developing treatments, the disorder continues to pose challenges. Nanoformulations represent a promising area of research that could lead to more effective and targeted therapies for epilepsy, although further studies are needed to address the associated challenges and fully realize their potential.

PET Imaging Using 89Zr Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention (EPR) in Prostate Cancer.

The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors, and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET-imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed-starPEG40kDa with or without talazoparib (TLZ), a potent PARPi, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared to CT26, a known EPR-high MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545, moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 subcutaneous xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in subcutaneous and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.

Fluorescent Protein PEGylation for Stable Photon Manipulation in Deep‐Red Light‐Emitting Devices

AbstractPEGylation is a classic strategy to reduce denaturation and immunogenicity in therapeutic proteins, bioimaging, and drug delivery. However, this concept has not been applied to incorporate biogenic materials as functional components in optoelectronics. Herein, PEGylation is rationalized as an effective tool to stabilize fluorescent proteins in solid‐state photon manipulation down‐converters integrated into bio‐hybrid light‐emitting diodes. In short, the archetypal red‐emitting protein mCherry is nonspecifically PEGylated with methoxypolyethylene glycols (mPEG) chains of different lengths (mPEG‐350/‐750/‐2000). These derivatives hold the same photoluminescence figures‐of‐merit of mCherry, but an improved resistance against organic solvents, pH, temperature, and polymers (in solution/dry‐coatings) upon increasing the mPEG length. Indeed, the best‐performing mCherry‐mPEG‐2000 adduct leads to deep‐red devices with threefold enhanced color stability (>300 h) under harsh operation conditions (150 mW cm−2) over the prior art. Different device architectures along with spectroscopic, thermocycling, and electrochemical impedance spectroscopy studies of the prepared coatings aid in rationalizing that PEGylation successfully reduces i) nonreversible thermal denaturation, ii) aggregation in solid‐state, and iii) photo‐induced oxidation and H+‐transfer deactivation of the chromophore, since oxygen diffusivity and H+‐reorganization across the protein skeleton are slowed down by strong H+‐bonding/hydrophobic mCherry‐mPEG interactions. Hence, this simple supramolecular modification is of utmost relevance for future advances in protein‐based optoelectronics.

Lipid-Based Nanoparticles as Drug Delivery System for Modern Therapeutics.

The emergence of lipid-based nanoparticulate systems has significantly reshaped the landscape of drug delivery. This review aims to encapsulate the advancements, challenges, and potential of lipid-based nanoparticulate drug delivery in modern therapeutics. Lipid-based nanoparticles, including liposomes, lipid nanoparticles, and solid lipid nanoparticles, harness the biocompatibility and biodegradability of lipids to encapsulate and deliver a diverse range of therapeutic agents. This platform offers solutions to various drug delivery challenges, such as enhancing drug solubility and bio- availability, achieving controlled and sustained release, targeted delivery, and co-delivery of multi-agents. These nanoparticles have demonstrated potential in overcoming biological barriers, including the blood-brain barrier, mucosal barriers, and cellular barriers, enabling the delivery of drugs to previously inaccessible sites. Biocompatibility and reduced toxicity are intrinsic attributes of lipid-based nanoparticles, minimizing immune responses and systemic toxicity while promoting personalized medicine possibilities. However, challenges in formulation, stability, and regulatory approval underscore the need for ongoing research and innovation in this field.

Graphene Quantum Dots from Natural Carbon Sources for Drug and Gene Delivery in Cancer Treatment

Cancer therapy is constantly evolving, with a growing emphasis on targeted and efficient treatment options. In this context, graphene quantum dots (GQDs) have emerged as promising agents for precise drug and gene delivery due to their unique attributes, such as high surface area, photoluminescence, up-conversion photoluminescence, and biocompatibility. GQDs can damage cancer cells and exhibit intrinsic photothermal conversion and singlet oxygen generation efficiency under specific light irradiation, enhancing their effectiveness. They serve as direct therapeutic agents and versatile drug delivery platforms capable of being easily functionalized with various targeting molecules and therapeutic agents. However, challenges such as achieving uniform size and morphology, precise bandgap engineering, and scalability, along with minimizing cytotoxicity and the environmental impact of their production, must be addressed. Additionally, there is a need for a more comprehensive understanding of cellular mechanisms and drug release processes, as well as improved purification methods. Integrating GQDs into existing drug delivery systems enhances the efficacy of traditional treatments, offering more efficient and less invasive options for cancer patients. This review highlights the transformative potential of GQDs in cancer therapy while acknowledging the challenges that researchers must overcome for broader application.

Recent Advancements in the Delivery of Therapeutic Agents Targeting RNA-dependent RNA Polymerase of SARS-CoV-2.

This study aimed to undertake a complete evaluation and analysis of all known data on RNA-dependent RNA polymerase (RdRp) inhibitors, concentrating on their safety, efficacy, and current improvements in the delivery of therapeutic drugs targeting RdRp of SARS-CoV-2. The work has attempted to emphasise the necessity for future research into the development of nanocarrier-based targeted drug delivery methods for RdRp inhibitors in the treatment of COVID-19. In December 2019, a novel SARS-- CoV-2 strain was discovered in Wuhan, China. SARS-CoV-2 is transferable among humans and has caused a global pandemic. The rapid global outbreak of SARS-CoV-2 and numerous deaths caused because of coronavirus disease (COVID-19) prompted the World Health Organization to announce a pandemic on March 12, 2020. COVID-19 is becoming a key concern that has a significant impact on an individual's life status. RdRp inhibitors are major pharmaceutical agents used in the treatment of COVID-19, which have various undesirable side effects, a greater risk of recurrence, lower bioavailability, as well as a lack of targeted therapy. Hence, the present article has provided a review on all known data on RdRp inhibitors, safety, and efficacy, and recent advances in the delivery of therapeutic agents targeting RdRp of SARS-CoV-2. An analysis has been done using a scientific data search engine, such as the National Center for Biotechnology Information (NCBI/PubMed), Science Direct, Google Scholar, WIPO, Lens, etc. The information has emphasized the need for more research into the safety, efficacy, and development of nanocarrier-based targeted drug delivery systems for RdRp inhibitors in the treatment of COVID-19.

Chemically Powered Nanomotors with Magnetically Responsive Function for Targeted Delivery of Exosomes.

Janus structure plays a crucial role in achieving chemically driven nanomotors with exceptional motion performance. However, Janus-structured chemically driven nanomotors with magnetic responsiveness are commonly fabricated by sputtering metal films. In the study, a self-assembly technique is employed to asymmetrically modify the surfaces of magnetic silica (SiO2@Fe3O4) nanoparticles with platinum nanoparticles, resulting in the formation of this kind nanomotors. Compared to platinumfilm, platinum nanoparticles exhibit a larger surface area and a higher catalytic activity. Hence, the nanomotors demonstrate improved diffusion capabilities at a significantly lower concentration (0.05%) of hydrogen peroxide (H2O2). Meanwhile, exosomes have gained attention as a potential tool for the efficient delivery of biological therapeutic drugs due to their biocompatibility. However, the clinical applications of exosomes are limited by their restricted tropism. The previously obtained nanomotors are utilized to deliver exosomes, greatly enhancing its targetability. The drug doxorubicin (DOX) is subsequently encapsulated within exosomes, acting as a representative drug model. Under the conditions of H2O2 concentration at the tumor site, the exosomes exhibited a significantly enhanced rate of entry into the breast cancercells. The utilization of the nanomotors for exosomes presents a novel approach in the development of hybrid chemically and magnetically responsive nanomotors.

Proteomic insights into breast cancer response to brain cell-secreted factors

The most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2 + and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2 + breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells, astrocytes, and microglia. Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines detected in the brain secretomes were supportive of inflammatory conditions, while the SKBR3 cells secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the exposure of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies.

Unveiling the Biomedical Applications of Zinc Oxide (ZnO) Nanoparticles: A Review Fostering on the Synthesis, Therapeutics and Imaging with Recent Developments

Zinc oxide nanoparticles (ZnO-NPs) in their many formulations have prompted an immense interest in nanomedicine and drug development. Numerous ZnO-NPs bioactive formulations demonstrate remarkable broad applications in deciphering their therapeutic effects and bioimaging. Their unique size, morphology-dependent properties and modifiable surface chemistry have made them promising candidates for translation into novel, alternative nanomedicines. ZnO-NPs demonstrate biocompatibility and are non-toxic with relatively required in-expensive production techniques. This review presents an in-depth comprehension of the synthesis, chemical and biological peculiarities of ZnO-NPs, including their varied manufacturing methods and their impactful applications in biomedicine. The physical, chemical and biological synthesis approaches that are unique for ZnO-NPs synthesis were comprehensively reviewed, followed by their applications in therapeutics (anticancer, antibacterial, drug delivery, skin treatment, antidiabetic and antioxidant), diagnostics (bioimaging and biosensor) and theranostics as well as their health hazards. ZnO-NPs exhibit antibacterial and anticancer activities, primarily through the liberation of zinc ions and generation of reactive oxygen species (ROS), which disrupt the cell membrane. Their anticancer properties are additionally apprised with an escalation in caspase 3/7 along with the modulation of pro- and anti-apoptotic proteins. ZnO-NPs are reviewed to attenuate hepatocellular carcinoma. Further, this article comprehended various in-vitro and in-vivo therapeutic effects of novel drug formulations of ZnO-NPs. It also delved into two fascinating areas: ZnO-NPs’ performance in comparison with other NPs and the potential of ZnO-NPs heterostructures with 2D nanomaterials. The goal of this review is to inspire further research efforts to meet the growing needs of next-generation nanomedicine.

Uncoated gold nanoparticles create fewer and less localized defects in model prokaryotic than in model eukaryotic lipid membranes

The rise of the populations of antibiotic resistant bacteria represents an increasing threat to human health. In addition to the synthesis of new antibiotics, which is an extremely expensive and time-consuming process, one of the ways to combat bacterial infections is the use of gold nanoparticles (Au NPs) as the vehicles for targeted delivery of therapeutic drugs. Since such a strategy requires the investigation of the effect of Au NPs (with and without drugs) on both bacterial and human cells, we investigated how the presence of coating-free Au NPs affects the physicochemical properties of lipid membranes that model prokaryotic (PRO) and eukaryotic (EU) cells. PRO/EU systems prepared as multilamellar liposomes (MLVs) and hybrid structures (HSs) from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG)/1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS) in the absence (MLVs)/presence (HSs) of differently distributed Au NPs (sizes ∼20 nm) reported stabilization of the gel phase of PRO systems in comparison with EU one (DSC data of PRO/EU were Tm(MLVs) ≈ 41.8 °C/42.0 °C, Tm¯ (HSs) ≈ 43.1 °C/42.4 °C, whereas UV-Vis response Tm(MLVs) ≈ 41.5 °C/42.0 °C, Tm¯ (HSs) ≈ 42.9 °C/41.1 °C). Vibrational spectroscopic data unraveled a substantial impact of Au NPs on the non-polar part of lipid bilayers, emphasizing the increase of kink and gauche conformers of the hydrocarbon chain. By interpreting the latter as Au NPs-induced defects, which exert the greatest effect when Au NPs are found exclusively outside the lipid membrane, these findings suggested that Au NPs reduced the compactness of EU-based lipid bilayers much more than in analogous PRO systems. Since the uncoated Au NPs manifested adverse effects when applied as antimicrobials, the results obtained in this work contribute towards recognizing AuNP functionalization as a strategy in tuning and reversing this effect.

Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability.

Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.

Robust G‐Quadruplex Dimer‐Guided Transmembrane DNA Nanovehicles for Targeted Payload Delivery

Here we report a robust G‐quadruplex (G4) dimer‐guided transmembrane DNA nanovehicle for targeted payload delivery, based on dimeric G4‐proximized aptamers that efficiently target transferrin receptors (TfR) over‐expressed on cancer cell surface. A monomolecular G4 (mono‐G4) named 93del that stably forms the interlocked dimeric structure is employed as the controlling module, which responds to environmental K+ and thereby holds two TfR aptamers at the proximity state. It endows the designed DNA system with over 3‐fold enhancement in cellular internalization, enabling the cancer‐specific delivery of fluorescent G4 ligands and therapeutic drugs for cellular imaging and treatment.

Transport cocktails for cancer therapeutics

Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, “delivery heterogeneity” crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40–80 µm), high energy (1–5 MeV) α particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such α-particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e., large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, “leaving no cancer cell behind.” We build first principles reaction-transport models (quantitatively informed by experiments) that explain the “geographically complementary” behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols. Published by the American Physical Society 2024

Hyaluronic acid-coated silver nanoparticles releasing Doxorubicin for combinatorial antitumor therapy

Although various nanocarriers have been developed to deliver anticancer drugs to the target tumors, it is still remaining great challenges, including burst release, non-specific targetability and insufficient therapeutic efficacy. Herein, we prepared a multifunctional nanoparticle composed of Ag core and hyaluronic acid shell (Ag NPs@HA) for stimultaneously intracellular delivery of Doxorubicin (DOX) and Ag NPs to improve the anticancer therapeutic efficacy. For our approach, Ag NPs was simply synthesized via the redox reaction between Ag+ ions and catechol group of functional HA, and DOX was subsequently loaded into the HA-coated Ag NPs through the interaction between the remaining catechol groups and DOX (Ag NPs@HA/DOX). The particles exhibited uniform morphology, good biocompatibility to normal cells, and pH-sensitive drug release. Notably, thanks to the specific interaction of HA and CD44 receptor-overexpressing cancer cells, Ag NPs@HA/DOX could dramatically improve the anti-tumor efficacy in vitro as well as in vivo mimicking 3D spheroid model, compared to the free DOX. Moreover, Ag NPs@HA/DOX exhibited superior tumor supression in vivo on a HELA-xenografted mouse model, while minimizing the systemic toxicity of free DOX. From the obtained results, we suggest Ag NPs@HA as potential nanocarrier for targeting delivery of various therapeutic drugs in anticancer therapy.

Core-Tunable Dendritic Polymer: A Folate-Guided Theranostic Nanoplatform for Drug Delivery Applications.

Clinical application of anticancer drugs is mostly limited due to their hydrophobic nature, which often results in lower bioavailability and lesser retention in systemic circulation. Despite extensive research on the development of targeted drug delivery systems for cancer treatment, delivery of hydrophobic therapeutic drugs to tumor cells remains a major challenge in the field. To address these concerns, we have precisely engineered a new hyperbranched polymer for the targeted delivery of hydrophobic drugs by using a malonic acid-based A2B monomer and 1,6-hexanediol. The choice of monomer systems in our design allows for the formation of higher molecular weight polymers with hydrophobic cavities for the efficient encapsulation of therapeutic drugs that exhibit poor water solubility. Using several experimental techniques such as NMR, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform-infrared (FT-IR), and gel permeation chromatography (GPC), the synthesized polymer was characterized, which indicated its dendritic structure, thermal stability, and amorphous nature, making it suitable as a drug delivery system. Following characterizations, theranostic nanoplatforms were formulated using a one-pot solvent diffusion method to coencapsulate hydrophobic drugs, BQU57 and doxorubicin. To achieve targeted delivery of loaded therapeutic drugs in A549 cancer cells, the surface of the polymeric nanoparticle was conjugated with folic acid. The therapeutic efficacy of the delivery system was determined by various cell-based in vitro experiments, including cytotoxicity, cell internalizations, reactive oxygen species (ROS), apoptosis, migration, and comet assays. Overall, findings from this study indicate that the synthesized dendritic polymer is a promising carrier for hydrophobic anticancer drugs with higher biocompatibility, stability, and therapeutic efficacy for applications in cancer therapy.

Self-modifying NanoEnhancers facilitating lysosomal escape for cGAS-STING cascading activation in tumor immunotherapy

Targeting mitochondria has emerged as an effective approach in recent tumor immunotherapy. While nanosized carriers have been utilized for therapeutic drug delivery, their retention in lysosomes diminishes their efficacy in targeting mitochondria. Despite the use of polycationic materials and peptides to facilitate lysosomal escape through the proton sponge effect and destabilization of lysosomal membranes, concerns persist regarding their stability and biocompatibility. Our objective is to exploit Oroxylin A (OA), a polyphenolic compound, to synthesize metal-polyphenolic complexes, capitalizing on OA's inherent lysosomal self-modifying properties to achieve efficient lysosomal escape. Herein, we report the fabrication of polyphenol-based OA@Mn@3-TYP nanoenhancers, assembled with hyaluronic acid (HA) and denoted as OMT NEs, designed for effective lysosomal escape and targeted drug delivery to mitochondria. These nanoenhancers exhibit a positive targeting ability towards tumor cells and facilitate lysosomal escape through spontaneous glucuronidation and sialic acid transporter mechanisms. The incorporation of OA and 3-TYP in the nanoenhancers leads to a cascading effect resulting in mitochondrial dysfunction and subsequent release of mitochondrial DNA (mtDNA). Upon activation of the Mn2+-enhanced cGAS-STING pathway by the released mtDNA, a synergistic anti-PD-1 immunotherapy effect is augmented, ultimately enhancing anti-tumor treatment.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

Drug Targeting and Nanotherapeutic Advancement in the Treatment of Rheumatoid Arthritis: Recent Progress in Drug Delivery Systems.

Pain and swelling in the joints, increased synovial thickness, and bone and cartilage degeneration are all symptoms of Rheumatoid Arthritis (RA). Anti-rheumatic medications, which are used in conventional treatment plans for RA, need high doses, frequent administration, and long-term use, all of which increase the risk of major adverse effects and low patient compliance. Drug Delivery Systems (DDS) have been developed for RA treatment in an effort to avoid these obstacles and improve clinical efficacy. There have been many successful experimental RA models using these techniques. There has been a notable uptick in the study of RA nanotherapies as a prospective improvement over conventional systemic therapy. In order to overcome the limits of traditional treatments, researchers have begun looking into nanotherapeutic approaches, notably drug-delivery nanosystems. The precise delivery and concentration of therapeutic drugs in the affected regions are made possible by the passive or active targeting of systemic administration. Several new DDS for treating RA have been addressed here. Therefore, nanoscale drug delivery devices increase drug solubility and bioavailability while decreasing the need for higher doses.