Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Red blood cell membrane-coated functionalized Cu-doped metal organic framework nanoformulations as a biomimetic platform for improved chemo-/chemodynamic/photothermal synergistic therapy.

Nanoformulations for combining chemotherapy, chemodynamic therapy, and photothermal therapy have enormous potential in tumor treatment. Coating nanoformulations with cell membranes endows them with homologous cellular mimicry, enabling nanoformulations to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused multifunctional biomimetic nanoformulations based on Cu-doped zeolitic imidazolate framework-8 (ZIF-8). Hydroxycamptothecin (HCPT), a clinical anti-tumor drug, was encapsulated into ZIF-8, which was subsequently coated with polydopamine (PDA) and red blood cell membrane. The as-fabricated biomimetic nanoformulations showed an enhanced cell uptake in vitro and the potential to prolong blood circulation in vivo, producing effective synergistic chemotherapy, chemodynamic therapy, and photothermal therapy under the 808 nm laser irradiation. Together, the biomimetic nanoformulations showed a prolonged blood circulation and evasion of immune recognition in vivo to provide a bio-inspired strategy which may have the potential for the multi-synergistic therapy of breast cancer.

Red Blood Cell Membrane-Camouflaged Polydopamine and Bioactive Glass Composite Nanoformulation for Combined Chemo/Chemodynamic/Photothermal Therapy.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Natural polysaccharides and their derivatives as potential medical materials and drug delivery systems for the treatment of peripheral nerve injuries.

Peripheral nerve repair following injury is one of the most serious problems in neurosurgery. Clinical outcomes are often unsatisfactory and associated with a huge socioeconomic burden. Several studies have revealed the great potential of biodegradable polysaccharides for improving nerve regeneration. We review here the promising therapeutic strategies involving different types of polysaccharides and their bio-active composites for promoting nerve regeneration. Within this context, polysaccharide materials widely used for nerve repair in different forms are highlighted, including nerve guidance conduits, hydrogels, nanofibers and films. While nerve guidance conduits and hydrogels were used as main structural scaffolds, the other forms including nanofibers and films were generally used as additional supporting materials. We also discuss the issues of ease of therapeutic implementation, drug release properties and therapeutic outcomes, together with potential future directions of research.

Porcupine-inspired microneedles coupled with an adhesive back patching as dressing for accelerating diabetic wound healing.

Diabetes chronic wound is a severe and frequently occurring medical issue in patients with diabetes that often leads to more serious complications. Microneedles (MNs) can be used for wound healing as they can effectively pierce the epidermis and inject drugs into the wound tissue. However, common MN patches cannot provide sufficient skin adhesion to prevent detachment from the wound area. Inspired by the barb hangnail microstructure of porcupine quills, a porcupine quill-like multilayer MN patch with an adhesive back patching for tissue adhesion and diabetic wound healing was designed. Sodium hyaluronate-modified CaO2 nanoparticles and metformin (hypoglycemic agent) were loaded into the polycaprolactone tips of MNs, endowing them with exceptional antibacterial ability and hypoglycemic effect. A flexible and adhesive back patching was formed by polyacrylamide-polydopamine/Cu2+ composite hydrogel, which ensures that the MN patches do not peel off from the application sites and reduce bacterial infection. The bioinspired multilayer structure of MN patches exhibits satisfactory mechanical and antibacterial properties, which is a potential multifunctional dressing platform for promoting wound healing. STATEMENT OF SIGNIFICANCE: The porcupine quill-like microneedles (MNs) with PAM-PDA/Cu2+ (PPC) composite hydrogel back patching have been fabricated, which can enhance the adhesion property of MNs to the skin through a physical interlock of multilayer MNs and chemical bonding of hydrogel patching. CaO2-HA NPs and metformin were loaded into the polycaprolactone tips of MNs, endowing them with the exceptional antibacterial ability and hypoglycemic effect, which could accelerate diabetic wound healing. As a safe and effective strategy in transdermal delivery of drugs, the as-fabricated flexible multilayer MN patch with good antibacterial, hypoglycemic, and biocompatibility has been used to promote the healing of diabetic wound by releasing oxygen and inhibiting inflammation at the wound site.

Transdermal delivery of allopurinol to acute hyperuricemic mice via polymer microneedles for the regulation of serum uric acid levels.

Allopurinol (AP) is widely used to treat hyperuricemia which may cause severe side effects upon oral administration. Alternative means for the treatment of hyperuricemia are demanded to simultaneously facilitate drug absorption, patient compliance, and fewer side effects. In this study, a new polymer microneedle (MN) system was developed for the transdermal delivery of AP to acute hyperuricemic mice. This study aims to achieve the controllable regulation of serum uric acid (SUA) levels with fewer side effects compared with oral administration. The matrix of polymer MNs consisted of polyvinylpyrrolidone (PVP) and polycaprolactone (PCL), in which the rapid dissolution of PVP offers a rapid dissolution of AP into the blood and the biodegradability of PCL resulting in a sustainable drug release behavior. An in vivo study demonstrated that the AP-loaded MN system can effectively reduce the SUA levels as oral administration with lower side effects, which will be conducive to reducing the adverse reactions and improving the bioavailability of AP. This MN-mediated strategy can facilitate transcutaneous hyperuricemia treatment and provide a new alternative for the exploration of clinical treatment of hyperuricemia and improvement of patient compliance.

Chitosan - dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics.

The development of synergistic drug combinations is a promising strategy for effective cancer suppression. Here, we report all-polysaccharide biodegradable polyelectrolyte complex hydrogels (DPCS) based on dextran phosphate carbamate (DP) and chitosan (CS) for controlled co-delivery of the anticancer drug doxorubicin (DOX) and the non-steroidal anti-inflammatory drug indomethacin (IND). IND can induce more apoptosis in tumor cells by reducing the level of multidrug resistance-associated protein 1. Based on calculations using density functional theory and zeta potential analysis data, carriers with high drug loading were obtained. The release profile of both drugs from the hydrogels was tuned by changing the molecular weight and functional groups content of the polysaccharides. The optimized DPCS showed a steady release of DOX both in vitro and in vivo, and a gradual release of IND, which constantly induced the action of DOX. Considering all of these benefits, DOX- and IND-loaded DPCS offer a promising long-acting polysaccharide-based antitumor platform.

Design of 3D polycaprolactone/ε-polylysine-modified chitosan fibrous scaffolds with incorporation of bioactive factors for accelerating wound healing.

Electrospun nanofibrous scaffolds show great application potentials for wound healing owing to their effective simulation of extracellular matrix (ECM). Three-dimensional (3D) nanofibrous dressings exhibit relatively high specific surface areas, better mimicry of native ECM, adjustable hydrophilicity and breathability, good histocompatibility, enhanced wound healing, and reduced inflammation. In the present work, we designed the 3D polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) nanofibrous scaffolds by an electrospinning and gas foaming process. Then, gelatin and heparin (Gel/Hep) were assembled onto the surface of PCL/PCS nanofibers by electrostatic adsorption, and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into Gel/Hep layer to form a multifunctional 3D nanofibrous scaffold (PCL/PCS@Gel/Hep+VEGF) for accelerating wound healing. The as-fabricated 3D PCL/PCS@GEL/Hep+VEGF nanofibrous scaffold showed excellent antibacterial ability, hemocompatibility and biocompatibility in vitro and wound healing ability in vivo. Immunological analysis showed that the as-fabricated nanofibrous scaffold inhibited inflammation at the wound sites while promoting angiogenesis during the wound healing process. STATEMENT OF SIGNIFICANCE: The electrospun 3D fibrous scaffolds using polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) have been fabricated as backbone for mimicking the extracellular matrix (ECM). Gelatin and heparin (Gel/Hep) were wrapped onto the surface of PCL/PCS fibers by electrostatic adsorption and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into surface Gel/Hep layer to form multifunctional 3D fibrous scaffolds. The as-fabricated multifunctional 3D fibrous scaffolds with good antibacterial ability and biocompatibility have been used as dressings for accelerating wound healing by inhibiting inflammation at the wound sites while promoting angiogenesis during the wound healing process.

Fabrication of Curcumin-Loaded Silk Fibroin and Polyvinyl Alcohol Composite Hydrogel Films for Skin Wound Healing.

Skin regeneration of full-thickness wounds remains a challenge, requiring a well-regulated interplay of cell-cell and cell-matrix signaling. Herein, the composite hydrogel films composed of silk fibroin (SF) and polyvinyl alcohol (PVA) as scaffolds loaded with curcumin nanoparticles (Cur NPs) were developed for skin wound healing. The structure and physicochemical properties of hydrogel films were first evaluated by scanning electron microscopy (SEM), water contact angle, and chemical and mechanical measurements. In addition, the as-fabricated composite hydrogel films have a unique 3D structure and excellent biocompatibility that facilitates the adhesion and growth of cells. Antimicrobial tests in vitro showed that they could inhibit the growth of bacteria due to the incorporation of Cur NPs into composite hydrogel films. The efficacy of the curcumin-loaded SF/PVA composite hydrogel films for skin wound healing was investigated on the skin defect model in vivo. Immunological analysis showed that the as-fabricated Cur NP-loaded SF/PVA composite hydrogel films inhibited inflammation at the wound sites, while promoting angiogenesis during the wound healing process.

Rational design of flexible microneedles coupled with CaO2@PDA-loaded nanofiber films for skin wound healing on diabetic rats.

Skin ulcers are one of the complications of diabetes. At present, the treatment of diabetic skin wounds is still not satisfactory, and the efficiency of drug delivery is limited by the depth of penetration. Herein, a synergistically flexible microneedle dressing is presented for effectively promoting diabetic wound healing. Metformin, as an anti-diabetic drug, can be loaded into microneedles, which can effectively pierce into the skin of diabetic rats to trigger a response for regulating blood glucose levels. A novel multifunctional nanosystem CaO2@polydopamine (CaO2@PDA) was introduced into polycaprolactone and gelatin (PCL/Gel) electrospun nanofiber films as microneedle back patches to inhibit inflammation, provide oxygen, and absorb the excess exudate. Besides, the CaO2@PDA in back patches also provided effective antibacterial properties against both S. aureus and E. coli. Additionally, the as-fabricated flexible microneedle dressings loaded with metformin and CaO2@PDA nanoparticles demonstrated a high level of CD31 and low level of TNF-α, leading to accelerated diabetic skin-wound closure. These distinctive features demonstrate that our microneedle system can be a facile candidate for efficient wound healing in patients with diabetes and may be applied in various biomedical fields.

Recent Advances in Polymer Microneedles for Drug Transdermal Delivery: Design Strategies and Applications.

In recent years, transdermal drug delivery based on microneedles (MNs) technology has received extensive attention, which offers a safer and painless alternative to hypodermic needle injections. They can pierce the stratum corneum and deliver drugs to the epidermis and dermis-structures of skin, showing prominent properties such as minimally invasiveness, bypassing first-pass metabolism, and can be self-administered. A range of materials has been used to fabricate MNs, such as silicon, metal, glass, and polymers. Among them, polymer MNs have gained increasing attention from pharmaceutical and cosmetic companies as one of the promising drug delivery methods. MN products have recently become available on the market, and some of them are under evaluation for efficacy and safety. This paper focuses on the current state of polymer MNs in drug transdermal delivery. The materials and methods for the fabrication of polymer MNs and their drug administration are described. The recent progress of polymer MNs for treatment of cancer, vaccine delivery, blood glucose regulation, androgenetic alopecia, obesity, tissue healing, myocardial infarction, and gout are reviewed. The challenges of MNs technology are summarized and the future development trend of MNs is also prospected.

Bacterial Cellulose-Based Nanocomposites Containing Ceria and Their Use in the Process of Stem Cell Proliferation.

A technique for the fabrication of bacterial cellulose-based films with CeO2 nanofiller has been developed. The structural and morphological characteristics of the materials have been studied, their thermal and mechanical properties in dry and swollen states having been determined. The preparation methodology makes it possible to obtain composites with a uniform distribution of nanoparticles. The catalytic effect of ceria, regarding the thermal oxidative destruction of cellulose, has been confirmed by TGA and DTA methods. An increase in CeO2 content led to an increase in the elastic modulus (a 1.27-fold increase caused by the introduction of 5 wt.% of the nanofiller into the polymer) and strength of the films. This effect is explained by the formation of additional links between polymer macro-chains via the nanoparticles' surface. The materials fabricated were characterized by a limited ability to swell in water. Swelling caused a 20- to 30-fold reduction in the stiffness of the material, the mechanical properties of the films in a swollen state remaining germane to their practical use. The application of the composite films in cell engineering as substrates for the stem cells' proliferation has been studied. The increase in CeO2 content in the films enhanced the proliferative activity of embryonic mouse stem cells. The cells cultured on the scaffold containing 5 wt.% of ceria demonstrated increased cell survival and migration activity. An analysis of gene expression confirmed improved cultivation conditions on CeO2-containing scaffolds.

Biodegradable polyelectrolyte complexes of chitosan and partially crosslinked dextran phosphate with potential for biomedical applications.

Polyelectrolyte complexes (PECs) are spontaneously formed by mixing oppositely charged polyelectrolyte solutions without the use of organic solvents and chemical crosslinkers are great candidate carriers for drug delivery. Herein, biodegradable antimicrobial polyelectrolyte complexes of chitosan - dextran phosphate (DPCS) containing cefazolin were developed and characterized in order to assess their suitability for biomedical applications. For this purpose, the simultaneous partial crosslinking and functionalization of dextran with phosphoric acid in a urea melt under reduced pressure were studied. The functional group content and molecular weight of dextran phosphate were varied in order to establish their influence on gel fraction yield, thermal properties and morphologies of the hydrogels. The stoichiometric PECs of DPCS showed good in vitro biocompatibility, pH sensitivity and biodegradability depending on the hydrogel composition. The release of drug from cefazolin-loaded DPCS hydrogels was through non-Fickian diffusion and displayed long sustained-release time. The drug-loaded hydrogels showed antimicrobial activity against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. The tunable degradation behavior under physiological conditions in combination with biocompatibility of the pristine DPCS and high antibacterial efficacy drug-loaded hydrogels may render the presented materials interesting for biomedical applications.

Fabrication of oxidized bacterial cellulose by nitrogen dioxide in chloroform/cyclohexane as a highly loaded drug carrier for sustained release of cisplatin.

Carboxylated bacterial cellulose (OBC) was fabricated by oxidation with nitrogen dioxide in chloroform/cyclohexane and employed as a carrier for sustained release of antitumor substance cisplatin (CDDP). The influence of removing water method, solvent used in the synthesis, concentration of N2O4, and duration of the oxidation on content of carboxyl groups in reaction products was established. Due to the possibility of nitrogen dioxide to penetrate into cellulose crystallites, the carboxyl group content of the OBC reaches high values up to 4 mmol/g. In vitro degradation of OBC was determined under simulated physiological conditions. The immobilization of CDDP on OBC was studied in detail. The initial burst release of the drug from the polymer was depressed. The cytotoxicity of CDDP-loaded OBC was evaluated with HeLa cells. The unique structure and properties of OBC make it a great candidate as drug delivery carrier.

Biodegradable pH-sensitive prospidine-loaded dextran phosphate based hydrogels for local tumor therapy.

The paper focuses on the development of drug delivery systems based on hydrogels of dextran phosphate (DP) for local cancer therapy. The hydrogels were characterized by physicochemical properties including functional group content, morphology, gel fraction, pH-responsive swelling. The desirable pH-sensitive drug release behavior of these hydrogels was demonstrated by a drug release test with Prospidine-loaded hydrogels (DP-Pr hydrogels) at different pH values. In vitro degradation of the DP-Pr hydrogels was determined under simulated physiological conditions. The cytotoxicity of the blank DP hydrogels and DP-Pr hydrogels with different Pr concentrations was evaluated with HeLa and HЕр-2 cells. Investigations of antitumor efficiency in vivo showed that administration of DP-Pr hydrogels in comparison with an aqueous solution of Pr results in the increase of antitumor activity, prolongation of therapeutic action and growth of a number of animals cured. Therefore, such pH-responsive DP hydrogels could be promising candidates as drug delivery carriers.