TiO2 nanotubes with customized diameters for local drug delivery systems.

In this study, we evaluated the drug release behavior of diameter customized TiO2 nanotube layers fabricated by anodization with various applied voltage sequences: conventional constant applied potentials of 20 V (45 nm) and 60 V (80 nm), a 20/60 V stepped potential (50 nm [two-diameter]), and a 20-60 V swept potential (49 nm [full-tapered]) (values in parentheses indicate the inner tube diameter at the top part of nanotube layers). The structures of the 50 nm (two-diameter) and 49 nm (full-tapered) samples had smaller inner diameters at the top part of nanotube layers than that of the 80 nm sample, while the outer diameters at the bottom part of nanotube layers were almost the same size as the 80 nm sample. The 80 nm sample, which had the largest nanotube diameter and length, exhibited the greatest burst release, followed by the 50 nm (two-diameter), 49 nm (full-tapered), and 45 nm samples. The initial burst released drug amounts and release rates from the 50 nm (two-diameter) and 49 nm (full-tapered) samples were significantly suppressed by the smaller tube top. On the other hand, the largest proportion of the slow released drug amount to the total released drug amount was observed for the 50 nm (two-diameter) sample. Thus, 50 nm (two-diameter) achieved suppressed initial burst release and large storage capacity. Therefore, this study has, for the first time, applied TiO2 nanotube layers with modulated diameters (two-diameter and full-tapered) to the realization of a localized drug delivery system (LDDS) with customized drug release properties.

Advanced Delivery Strategies of Nintedanib for Lung Disorders and Beyond: A Comprehensive Review.

Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib, inhibits multiple signalling receptors, including endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) and ultimately inhibits fibroblast proliferation and differentiation. Therefore, nintedanib has been studied widely for other ailments like cancers and hepatic fibrosis, apart from lung disorders. Commercially, nintedanib is available as soft gelatin capsules for treatment against idiopathic pulmonary fibrosis. Since it has very low oral bioavailability (4.7%), high doses of a drug, such as 100-150 mg, are administered, which can cause problems of gastrointestinal irritation and hepatotoxicity. The article begins with exploring the mechanism of action of nintedanib, elucidating its complex interactions within cellular pathways that govern fibrotic processes. It also emphasizes the pharmacokinetics of nintedanib, clinical trial insights, and the limitations of conventional formulations. The article mainly focuses on the emerging landscape of nanoparticle-based carriers such as hybrid liposome-exosome, nano liquid crystals, discoidal polymeric, and magnetic systems, offering promising avenues to optimize drug targeting, address its efficacy issues and minimise adverse effects. However, none of these delivery systems are commercialised, and further research is required to ensure safety and effectiveness in clinical settings. Yet, as research progresses, these advanced delivery systems promise to revolutionise the treatment landscape for various fibrotic disorders and cancers, potentially improving patient outcomes and quality of life.

Prostate tissue ablation and drug delivery by an image-guided injectable ionic liquid in ex vivo and in vivo models.

Benign prostatic hyperplasia and prostate cancer are often associated with lower urinary tract symptoms, which can severely affect patient quality of life. To address this challenge, we developed and optimized an injectable compound, prostate ablation and drug delivery agent (PADA), for percutaneous prostate tissue ablation and concurrently delivered therapeutic agents. PADA is an ionic liquid composed of choline and geranic acid mixed with anticancer therapeutics and a contrast agent. The PADA formulation was optimized for mechanical properties compatible with hand injection, diffusion capability, cytotoxicity against prostate cells, and visibility of an x-ray contrast agent. PADA also exhibited antibacterial properties against highly resistant clinically isolated bacteria in vitro. Ultrasound-guided injection, dispersion of PADA in the tissue, and tissue ablation were tested ex vivo in healthy porcine, canine, and human prostates and in freshly resected human tumors. In vivo testing was conducted in a murine subcutaneous tumor model and in the canine prostate. In all models, PADA decreased the number of viable cells in the region of dispersion and supported the delivery of nivolumab throughout a portion of the tissue. In canine survival experiments, there were no adverse events and no impact on urination. The injection approach was easy to perform under ultrasound guidance and produced a localized effect with a favorable safety profile. These findings suggest that PADA is a promising therapeutic prostate ablation strategy to treat lower urinary tract symptoms.

Recent Update on Nanocarrier(s) as the Targeted Therapy for Breast Cancer.

Despite ongoing advances in cancer therapy, the results for the treatment of breast cancer are not satisfactory. The advent of nanotechnology promises to be an essential tool to improve drug delivery effectiveness in cancer therapy. Nanotechnology provides an opportunity to enhance the treatment modality by preventing degradation, improving tumour targeting, and controlling drug release. Recent advances have revealed several strategies to prevent cancer metastasis using nano-drug delivery systems (NDDS). These strategies include the design of appropriate nanocarriers loaded with anti-cancer drugs that target the optimization of physicochemical properties, modulate the tumour microenvironment, and target biomimetic techniques. Nanocarriers have emerged as a preferential approach in the chemotropic treatment for breast cancer due to their pivotal role in safeguarding the therapeutic agents against degradation. They facilitate efficient drug concentration in targeted cells, surmount the resistance of drugs, and possess a small size. Nevertheless, these nanocarrier(s) have some limitations, such as less permeability across the barrier and low bioavailability of loaded drugs. To overcome these challenges, integrating external stimuli has been employed, encompassing infrared light, thermal stimulation, microwaves, and X-rays. Among these stimuli, ultrasound-triggered nanocarriers have gained significant attention due to their cost-effectiveness, non-invasive nature, specificity, ability to penetrate tissues, and capacity to deliver elevated drug concentrations to intended targets. This article comprehensively reviews recent advancements in different nanocarriers for breast cancer chemotherapy. It also delves into the associated hurdles and offers valuable insights into the prospective directions for this innovative field.

Improved efficacy of cisplatin delivery by peanut agglutinin­modified liposomes in non­small cell lung cancer.

Globally, non­small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre­preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP­loaded PNA­modified liposomes (CDDP­PNA­Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP­PNA­Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti­tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)­loaded PNA­modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP­PNA­Lip resulted in a 2.65­fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand­modified liposomes may significantly improve its tumour­targeting capabilities, providing valuable insights for clinical drug development.

An intelligent Cu/ZIF-8-based nanodrug delivery system for tumor-specific and synergistic therapy via tumor microenvironment-responsive cascade reaction.

An intelligent nanodrug delivery system (Cu/ZIF-8@GOx-DOX@HA, hereafter CZGDH) consisting of Cu-doped zeolite imidazolate framework-8 (Cu/ZIF-8, hereafter CZ), glucose oxidase (GOx), doxorubicin (DOX), and hyaluronic acid (HA) was established for targeted drug delivery and synergistic therapy of tumors. The CZGDH specifically entered tumor cells through the targeting effect of HA and exhibited acidity-triggered biodegradation for subsequent release of GOx, DOX, and Cu2+ in the tumor microenvironment (TME). The GOx oxidized the glucose (Glu) in tumor cells to produce H2O2 and gluconic acid for starvation therapy (ST). The DOX entered the intratumoral cell nucleus for chemotherapy (CT). The released Cu2+ consumed the overexpressed glutathione (GSH) in tumor cells to produce Cu+. The generated Cu+ and H2O2 triggered the Fenton-like reaction to generate toxic hydroxyl radicals (·OH), which disrupted the redox balance of tumor cells and effectively killed tumor cells for chemodynamic therapy (CDT). Therefore, synergistic multimodal tumor treatment via TME-activated cascade reaction was achieved. The nanodrug delivery system has a high drug loading rate (48.3 wt%), and the three-mode synergistic therapy has a strong killing effect on tumor cells (67.45%).

Genistein transfersome-embedded topical delivery system for skin melanoma treatment: in vitro and ex vivo evaluations.

Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; in vitro drug release; viscosity; pH; ex vivo anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.

Design of chitosan colon delivery micro/nano particles for an Achillea millefolium extract with antiproliferative activity against colorectal cancer cells.

In this study, chitosan low molecular weight (LCH) and chitosan medium molecular weight (MCH) were employed to encapsulate a yarrow extract rich in chlorogenic acid and dicaffeoylquinic acids (DCQAs) that showed antiproliferative activity against colon adenocarcinoma cells. The design of CH micro/nanoparticles to increase the extract colon delivery was carried out by using two different techniques: ionic gelation and spray drying. Ionic gelation nanoparticles obtained were smaller and presented higher yields values than spray-drying microparticles, but spray-drying microparticles showed the best performance in terms of encapsulation efficiency (EE) (> 94%), also allowing the inclusion of a higher quantity of extract. Spray-drying microparticles designed using LCH with an LCH:extract ratio of 6:1 (1.25 mg/mL) showed a mean diameter of 1.31 ± 0.21 µm and EE values > 93%, for all phenolic compounds studied. The release profile of phenolic compounds included in this formulation, at gastrointestinal pHs (2 and 7.4), showed for most of them a small initial release, followed by an increase at 1 h, with a constant release up to 3 h. Chlorogenic acid presented the higher release values at 3 h (56.91% at pH 2; 44.45% at pH 7.4). DCQAs release at 3 h ranged between 9.01- 40.73%, being higher for 1,5- and 3,4-DCQAs. After gastrointestinal digestion, 67.65% of chlorogenic and most DCQAs remained encapsulated. Therefore, spray-drying microparticles can be proposed as a promising vehicle to increase the colon delivery of yarrow phenolics compounds (mainly chlorogenic acid and DCQAs) previously described as potential agents against colorectal cancer.

Facile synthesis of elastin nanogels encapsulated decursin for castrated resistance prostate cancer therapy.

Nanogels offer hope for precise drug delivery, while addressing drug delivery hurdles is vital for effective prostate cancer (PCa) management. We developed an injectable elastin nanogels (ENG) for efficient drug delivery system to overcome castration-resistant prostate cancer (CRPC) by delivering Decursin, a small molecule inhibitor that blocks Wnt/ßcatenin pathways for PCa. The ENG exhibited favourable characteristics such as biocompatibility, flexibility, and low toxicity. In this study, size, shape, surface charge, chemical composition, thermal stability, and other properties of ENG were used to confirm the successful synthesis and incorporation of Decursin (DEC) into elastin nanogels (ENG) for prostate cancer therapy. In vitro studies demonstrated sustained release of DEC from the ENG over 120 h, with a pH-dependent release pattern. DU145 cell line induces moderate cytotoxicity of DEC-ENG indicates that nanomedicine has an impact on cell viability and helps strike a balance between therapeutics efficacy and safety while the EPR effect enables targeted drug delivery to prostate tumor sites compared to free DEC. Morphological analysis further supported the effectiveness of DEC-ENG in inducing cell death. Overall, these findings highlight the promising role of ENG-encapsulated decursin as a targeted drug delivery system for CRPC.

Rapamycin-encapsulated nanoparticle delivery in polycystic kidney disease mice.

Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.

An overview of lipid constituents in lipid nanoparticle mRNA delivery systems.

mRNA therapeutics have shown great potential for a broad spectrum of disease treatment. However, the challenges of mRNA's inherent instability and difficulty in cellular entry have hindered its progress in the biomedical field. To address the cellular barriers and deliver mRNA to cells of interest, various delivery systems are designed. Among these, lipid nanoparticles (LNPs) stand out as the most extensively used mRNA delivery systems, particularly following the clinical approvals of corona virus disease 2019 (COVID-19) mRNA vaccines. LNPs are comprised of ionizable cationic lipids, phospholipids, cholesterol, and polyethylene glycol derived lipids (PEG-lipids). In this review, we primarily summarize the recent advancements of the LNP mRNA delivery technology, focusing on the structures of four lipid constituents and their biomedical applications. We delve into structure-activity relationships of the lipids, while also exploring the future prospects and challenges in developing more efficacious mRNA delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Exosome for mRNA delivery: strategies and therapeutic applications.

Messenger RNA (mRNA) has emerged as a promising therapeutic molecule with numerous clinical applications in treating central nervous system disorders, tumors, COVID-19, and other diseases. mRNA therapies must be encapsulated into safe, stable, and effective delivery vehicles to preserve the cargo from degradation and prevent immunogenicity. Exosomes have gained growing attention in mRNA delivery because of their good biocompatibility, low immunogenicity, small size, unique capacity to traverse physiological barriers, and cell-specific tropism. Moreover, these exosomes can be engineered to utilize the natural carriers to target specific cells or tissues. This targeted approach will enhance the efficacy and reduce the side effects of mRNAs. However, difficulties such as a lack of consistent and reliable methods for exosome purification and the efficient encapsulation of large mRNAs into exosomes must be addressed. This article outlines current breakthroughs in cell-derived vesicle-mediated mRNA delivery and its biomedical applications.

Advances in polymeric nano-delivery systems targeting hair follicles for the treatment of acne.

Acne is a common chronic inflammatory disorder of the sebaceous gland in the hair follicle. Commonly used external medications cause skin irritation, and the transdermal capacity is weak, making it difficult to penetrate the cuticle skin barrier. Hair follicles can aid in the breakdown of this barrier. As nanomaterials progress, polymer-based nanocarriers are routinely used for hair follicle drug delivery to treat acne and other skin issues. Based on the physiological and anatomical characteristics of hair follicles, this paper discusses factors affecting hair follicle delivery by polymer nanocarriers, summarizes the common combination technology to improve the targeting of hair follicles by carriers, and finally reviews the most recent research progress of different polymer nanodrug-delivery systems for the treatment of acne by targeting hair follicles.

Co-delivery of oncolytic virus and chemotherapeutic modality: Vincristine against prostate cancer treatment: A potent viro-chemotherapeutic approach.

Prostate cancer is a prevalent carcinoma among males, and conventional treatment options are often limited. Cytotoxic chemotherapy, despite its drawbacks, remains a mainstay. We propose a targeted co-delivery approach using nanoscale delivery units for Oncolytic measles virus (OMV) and vincristine (VC) to enhance treatment efficacy. The HA-coated OMV + VC-loaded TCs nanoformulation is designed for targeted oncolytic activity in prostate cancer. The CD44 expression analysis in prostate cancer cell lines indicates a significantly high expression in PC3 cells. The optimization of nanoformulations using Design of Expert (DOE) is performed, and the preparation and characterization of HA-coated OMV + VC-loaded TCs nanoformulations are detailed showing average particle size 397.2 ± 0.01 nm and polydispersity index 0.122 with zeta potential 19.7 + 0.01 mV. Results demonstrate successful encapsulation efficiency with 2.4 × 106 TCID50/Ml and sustained release of OMV and VC from the nanoformulation for up to 72 h. In vitro, assays reveal potent anticancer activity at 10 ± 0.71% cell viability in PC3 cells compared to 73 ± 0.66% in HPrEC and significant morphological changes at 90 µg/ml in dose and time-dependent manner. The co-formulation showed positive cell death 49.5 ± 0.02% at 50 µg PI/ml in PBS and 54.3% cell cycle arrest at the G2/M phase, 8.1% G0/G1 and 5.7% at S phase, with significant mitochondrial membrane potential (MMP) at 50 µg/ml, as assessed by flow cytometry (FACS). The surface-integrating ligand approach enhances the targeted delivery of the oncolytic virus and chemotherapeutic drug, presenting a potential alternative for prostate cancer treatment and suggested that co-administering VC and OMV in a nanoformulation could improve therapeutic outcomes while reducing chemotherapeutic drug doses.

Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions.

Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins. We then demonstrate the capacity of select lipid tags to mediate increased EV loading and functional delivery of an engineered transcription factor to modulate gene expression in target cells. We envision that this technology could be leveraged to develop new EV-based therapeutics that deliver a wide array of macromolecular cargo.

Hematopoietic stem and progenitor cell membrane-coated vesicles for bone marrow-targeted leukaemia drug delivery.

Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin ß2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.

Growth Factors to Enhance Nerve Regeneration: Approaching Clinical Translation.

Following nerve injury, growth factors (GFs) are transiently upregulated in injured neurons, proliferating Schwann cells, and denervated muscle and skin. They act on these same cells and tissues to promote nerve regeneration and end-organ reinnervation. Consequently, much attention has been focused on developing GF-based therapeutics. A major barrier to clinical translation of GFs is their short half-life. To provide sustained GF treatment to the affected nerve, muscle, and skin in a safe and practical manner, engineered drug delivery systems are needed. This review highlights recent advancements in GF-based therapeutics and discusses the remaining hurdles for clinical translation.

Emerging Nanotechnology in Preclinical Pancreatic Cancer Immunotherapy: Driving Towards Clinical Applications.

The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy.

[Advances in Nanotechnology-Based Drug Delivery Systems in the Treatment of Hepatocellular Carcinoma].

Primary liver cancer is one of the most common malignant tumors of the digestive system,of which hepatocellular carcinoma (HCC) accounts for more than 90% of the total cases.The patients with early HCC treated by surgical resection generally demonstrate good prognosis.However,due to the insidious onset,HCC in the vast majority of patients has progressed to the mid-to-late stage when being diagnosed.As a result,surgical treatment has unsatisfactory effects,and non-surgical treatment methods generally have severe side effects and low tumor selectivity.Nanoparticles (NP) with small sizes,large specific surface areas,and unique physical and chemical properties have become potential carriers for the delivery of therapeutic agents such as drugs,genes,and cytokines.The nano-delivery systems with NP as the carrier can regulate the metabolism and transformation of drugs,genes,and cytokines in vivo from time,space,and dose via functional modification,showing great potential in the treatment of HCC.This paper introduces the current status and advantages of several common nano-delivery systems,including organic nano-carriers,inorganic nano-carriers,and exosomes,in the treatment of HCC.Furthermore,this paper summarizes the mechanisms of NP-based nano-carriers in treating HCC and provides reference for the development of new nano-delivery systems.