Enhanced Skin Permeation of 5-Fluorouracil through Drug-in-Adhesive Topical Patches.

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug release and improved patient compliance. Our study highlights the development of Eudragit® E (EuE)-based drug-in-adhesive (DIA) patches containing a clinically significant high level of 5-FU (approximately 450 µg/cm2) formulated with various chemical permeation enhancers. The patches containing Transcutol® (Patch-TRAN) or oleic acid (Patch-OA) demonstrated significantly higher skin penetration ex vivo than their control counterpart, reaching 5-FU concentrations of 76.39 ± 27.7 µg/cm2 and 82.56 ± 8.2 µg/cm2, respectively. Furthermore, the findings from in vitro permeation studies also validated the superior skin permeation of 5-FU achieved by Patch-OA and Patch-TRAN over 72 h. Moreover, the EuE-based DIA patch platform demonstrated suitable adhesive and mechanical properties with an excellent safety profile evaluated through an inaugural in vivo human study involving 11 healthy volunteers. In conclusion, the DIA patches could be a novel alternative option for NMSC as the patches effectively deliver 5-FU into the dermis layer and receptor compartment ex vivo for an extended period with excellent mechanical and safety profiles.

Printing a cure: A tailored solution for localized drug delivery in liver cancer treatment.

Adjuvant chemotherapy is highly recommended for liver cancer to enhance survival rates due to its tendency to recur frequently. Localized drug-eluting implants have gained traction as an alternative to overcome the limitations of systemic chemotherapy. This work describes the development of biodegradable 3D printed (3DP) bilayer films loaded with 5-fluorouracil (5FU) and cisplatin (Cis) with different infill percentages where the 5FU layers were 40%, 30%, and 30% and Cis layers were 10%, 15%, and 10% for films A, B, and C, respectively. The relevant characterization tests were performed, and the drug content of films was 0.68, 0.50, and 0.50 mg of 5FU and 0.39, 0.80, and 0.34 mg of Cis for films A, B, and C, respectively. Cis release was affected by the alterations to the film design, where films A, B, and C showed complete release at 12, 14, and 23 days, respectively. However, 5FU was released over 24 h for all films. The films were stable for up to two weeks after storage at 25 °C/65% relative humidity and four weeks at 4 °C where drug content, tensile strength, FTIR, and thermal analysis results demonstrated negligible alterations. The cytotoxicity of the films was assessed by MTS assays using HepG2 cell lines demonstrating up to 81% reduction in cell viability compared to blank films. Moreover, apoptosis was confirmed by Western Blots and the determination of mitochondrial cell potential, highlighting the potential of these films as a promising approach in adjuvant chemotherapy.

Innovative Topical Patches for Non-Melanoma Skin Cancer: Current Challenges and Key Formulation Considerations.

Non-melanoma skin cancer (NMSC) is the most prevalent malignancy worldwide, with approximately 6.3 million new cases worldwide in 2019. One of the key management strategies for NMSC is a topical treatment usually utilised for localised and early-stage disease owing to its non-invasive nature. However, the efficacy of topical agents is often hindered by poor drug penetration and patient adherence. Therefore, various research groups have employed advanced drug delivery systems, including topical patches to overcome the problem of conventional topical treatments. This review begins with an overview of NMSC as well as the current landscape of topical treatments for NMSC, specifically focusing on the emerging technology of topical patches. A detailed discussion of their potential to overcome the limitations of existing therapies will then follow. Most importantly, to the best of our knowledge, this work unprecedentedly combines and discusses all the current advancements in innovative topical patches for the treatment of NMSC. In addition to this, the authors present our insights into the key considerations and emerging trends in the construction of these advanced topical patches. This review is meant for researchers and clinicians to consider utilising advanced topical patch systems in research and clinical trials toward localised interventions of NMSC.

Application of Exogenous GnRH in Food Animal Production.

Over several decades, exogenous GnRH and agonists have been employed for controlling reproductive cascades in animals, and treating some reproductive morbidities. The administration of GnRH is used in animals to counter ovarian dysfunction, induce ovulation, and to increase conception and pregnancy rates. GnRH and its agonists are used in the treatment of cystic ovarian degeneration and repeat breeder syndrome. The development of protocols for GnRH administration by intramuscular injection, intramuscular or subcutaneous implants, and intravaginal deposition has empowered their clinical use worldwide. Currently, exogenous GnRH products are a central part of several pre- and post-breeding programs for the enhancement of fertility, including the control of estrous cycles and timing of ovulation, development of fixed-time artificial insemination protocols, improved embryo survival, and the treatment of reproductive morbidity. The aim of the present review is to summarize the application of exogenous GnRH agonists in food animal production.

Development and Optimization of Imiquimod-Loaded Nanostructured Lipid Carriers Using a Hybrid Design of Experiments Approach.

Background: Imiquimod (IMQ) is an immunomodulating drug that is approved for the treatment of superficial basal cell carcinoma, actinic keratosis, external genital warts and perianal warts. However, IMQ cream (Aldara®) has several drawbacks including poor skin permeation, local toxicity, and compromised patient compliance as a topical pharmacological option. Methods: Our research aimed to develop and optimize nanostructured lipid carriers (NLCs) containing IMQ for the first time using a hybrid design of experiments approach. The optimized formulation was then incorporated into a matrix-type topical patch as an alternative dosage form for topical application and evaluated for IMQ deposition across different skin layers in comparison to the performance of the commercial product. Additionally, our work also attempted to highlight the possibility of implementing environment-friendly practices in our IMQ-NLCs formulation development by reviewing our analytical methods and experimental designs and reducing energy and solvent consumption where possible. Results: In this study, stearyl alcohol, oleic acid, Tween® 80 (polysorbate 80), and Gelucire® 50/13 (Stearoyl polyoxyl-32 glycerides) were selected for formulation development. The formulation was optimized using a 2k factorial design and a central composite design. The optimized formulation achieved the average particle size, polydispersity index, and zeta potential of 75.6 nm, 0.235, and - 30.9 mV, respectively. Subsequently, a matrix-type patch containing IMQ-NLCs was developed and achieved a statistically significant improvement in IMQ deposition in the deeper skin layers. The IMQ deposition from the patch into the dermis layer and receptor chamber was 3.3 ± 0.9 µg/cm2 and 12.3 ± 2.2 µg/cm2, while the commercial cream only deposited 1.0 ± 0.8 µg/cm2 and 1.5 ± 0.5 µg/cm2 of IMQ, respectively. Conclusion: In summary, IMQ-NLC-loaded patches represent great potential as a topical treatment option for skin cancer with improved patient compliance.

pH and its applications in targeted drug delivery.

Physiologic pH is vital for the normal functioning of tissues and varies in different parts of the body. The varying pH of the body has been exploited to design pH-sensitive smart oral, transdermal and vaginal drug delivery systems (DDS). The DDS demonstrated promising results in hard-to-treat diseases such as cancer and Helicobacter pylori infection. In some cases, a change in pH of tissues or body fluids has also been employed as a useful diagnostic biomarker. This paper aims to comprehensively review the development and applications of pH-sensitive DDS as well as recent advances in the field.

Effect of plasticizers on drug-in-adhesive patches containing 5-fluorouracil.

Topical patches containing 5-fluorouracil (5-FU) are a feasible alternative to overcome the shortcomings of commercial cream for the treatment of non-melanoma skin cancer (NMSC). Plasticizers are a critical component of drug-in-adhesive (DIA) patches as they can significantly affect the mechanical, adhesive and drug release characteristics of the patches. Eudragit® E (EuE) is a methacrylate-based cationic copolymer capable of producing flexible and adhesive films for topical application. In this study, the effect of plasticizers on the mechanical, adhesive and 5-FU release characteristics of EuE-based patches was comprehensively evaluated. While the elongation at break (%) and adhesion of the films were significantly increased with increasing triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) concentrations, the tensile strength showed an inverse relationship. EuE plasticized with 40% triacetin, 30% DBS or 40% w/w TEC produced elastic and adhesive films most suitable for topical application. In vitro release studies of the 5-FU-loaded patches demonstrated an initial burst release pattern during the first 10 min followed by a slow release over 120 min. In summary, this study provides important information on effect of plasticizers for preparation of EuE-based patches with desired mechanical, adhesive and release characteristics of 5-FU towards their potential application in the treatment of NMSC.

Three-Dimensional Printing for Cancer Applications: Research Landscape and Technologies.

As a variety of novel technologies, 3D printing has been considerably applied in the field of health care, including cancer treatment. With its fast prototyping nature, 3D printing could transform basic oncology discoveries to clinical use quickly, speed up and even revolutionise the whole drug discovery and development process. This literature review provides insight into the up-to-date applications of 3D printing on cancer research and treatment, from fundamental research and drug discovery to drug development and clinical applications. These include 3D printing of anticancer pharmaceutics, 3D-bioprinted cancer cell models and customised nonbiological medical devices. Finally, the challenges of 3D printing for cancer applications are elaborated, and the future of 3D-printed medical applications is envisioned.

Three-Dimensional Printing of Curcumin-Loaded Biodegradable and Flexible Scaffold for Intracranial Therapy of Glioblastoma Multiforme.

A novel drug delivery system preventing Glioblastoma multiforme (GBM) recurrence after resection surgery is imperatively required to overcome the mechanical limitation of the current local drug delivery system and to offer personalised treatment options for GBM patients. In this study, 3D printed biodegradable flexible porous scaffolds were developed via Fused Deposition Modelling (FDM) three-dimensional (3D) printing technology for the local delivery of curcumin. The flexible porous scaffolds were 3D printed with various geometries containing 1, 3, 5, and 7% (w/w) of curcumin, respectively, using curcumin-loaded polycaprolactone (PCL) filaments. The scaffolds were characterised by a series of characterisation studies and in vitro studies were also performed including drug release study, scaffold degradation study, and cytotoxicity study. The curcumin-loaded PCL scaffolds displayed versatile spatiotemporal characteristics. The polymeric scaffolds obtained great mechanical flexibility with a low tensile modulus of less than 2 MPa, and 4 to 7-fold ultimate tensile strain, which can avoid the mechanical mismatch problem of commercially available GLIADEL wafer with a further improvement in surgical margin coverage. In vitro release profiles have demonstrated the sustained release patterns of curcumin with adjustable release amounts and durations up to 77 h. MTT study has demonstrated the great cytotoxic effect of curcumin-loaded scaffolds against the U87 human GBM cell line. Therefore, 3D printed curcumin-loaded scaffold has great promise to provide better GBM treatment options with its mechanical flexibility and customisability to match individual needs, preventing post-surgery GBM recurrence and eventually prolonging the life expectancy of GBM patients.

Pharmaceutical Development of 5-Fluorouracil-Eluting Stents for the Potential Treatment of Gastrointestinal Cancers and Related Obstructions.

BACKGROUND: Drug-eluting gastrointestinal (GI) stents are emerging as promising platforms for the treatment of GI cancers and provide the combined advantages of mechanical support to prevent lumen occlusion and as a reservoir for localized drug delivery to tumors. Therefore, in this work we present a detailed quality assurance study of 5-fluorouracil (5FU) drug-eluting stents (DESs) as potential candidates for the treatment of obstructive GI cancers. METHODS: The 5FU DESs were fabricated via a simple two-step sequential dip-coating process of commercial GI self-expanding nitinol stents with a 5FU-loaded polyurethane basecoat and a drug-free protective poly(ethylene-co-vinyl acetate) topcoat. The drug loading, content uniformity and drug stability were determined using a validated high-performance liquid chromatography (HPLC) method, which is also recommended in the United States Pharmacopeia. In vitro drug release studies were performed in phosphate buffered saline to determine the drug releasing properties of the two 5FU-loaded stents. Gas chromatography (GC) and HPLC were employed to determine total residual tetrahydrofuran and N,N-dimethylformamide in the stents remaining from the manufacturing process. Sterilization of the stents was performed using gamma radiation and stability testing was carried out for 3 months. RESULTS: The drug loading analysis revealed excellent uniformity in the distribution of 5FU between and within individual stents. Determination of drug stability in the biorelevant release media confirmed that 5FU remains stable over 100 d. In vitro drug release studies from the stents revealed sustained release of 5FU across two different time scales (161 and 30 d), and mathematical modeling of drug release profiles revealed a diffusion-controlled mechanism for the sustained 5FU release. GC and HPLC analysis revealed that the daily residual solvent leached from the stents was below the United States (US) Food and Drug Administration (FDA) guidelines, and therefore, unlikely to cause localized/systemic toxicities. Sterilization of the stents with gamma radiation and accelerated stability tests over a period of 3 months revealed no significant effect on the stability or in vitro release of 5FU. CONCLUSION: Our results demonstrate that the 5FU DESs meet relevant quality standards and display favourable drug release characteristics for the potential treatment of GI cancers and related obstructions.

Drug-Loaded, Polyurethane Coated Nitinol Stents for the Controlled Release of Docetaxel for the Treatment of Oesophageal Cancer.

For several decades, self-expanding metal stents (SEMSs) have shown significant clinical success in the palliation of obstructive metastatic oesophageal cancer. However, these conventional oesophageal stents can suffer from stent blockage caused by malignant tumour cell growth. To overcome this challenge, there is growing interest in drug-releasing stents that, in addition to palliation, provide a sustained and localized release of anticancer drugs to minimise tumour growth. Therefore, in this study we prepared and evaluated an oesophageal stent-based drug delivery platform to provide the sustained release of docetaxel (DTX) for the treatment of oesophageal cancer-related obstructions. The DTX-loaded oesophageal stents were fabricated via dip-coating of bare nitinol stents with DTX-polyurethane (PU) solutions to provide PU coated stents with DTX loadings of 1.92 and 2.79% w/w. Mechanical testing of the DTX-PU coated stents revealed that an increase in the drug loading resulted in a reduction in the ultimate tensile strength, toughness and Young's modulus. In vitro release studies showed a sustained release of DTX, with ~80-90% released over a period of 33 days. While the DTX-loaded stents exhibited good stability to gamma radiation sterilisation, UV sterilisation or accelerated storage at elevated temperatures (40 °C) resulted in significant DTX degradation. Cell proliferation, apoptosis and Western blotting assays revealed that the DTX released from the stents had comparable anticancer activity to pure DTX against oesophageal cancer cells (KYSE-30). This research demonstrates that the dip-coating technique can be considered as a promising approach for the fabrication of drug-eluting stents (DESs) for oesophageal cancer treatment.

Engineering of a dual-modal phototherapeutic nanoplatform for single NIR laser-triggered tumor therapy.

Theranostic nanoplatforms integrating simultaneously photodynamic therapy (PDT) and photothermal therapy (PTT) exhibit intrinsic advantages in tumor therapy due to distinct mechanisms of action. However, it is challenging to achieve PDT and PTT under single near-infrared (NIR) laser irradiation with a nanoplatform utilizing conventional organic photodynamic agent and inorganic photothermal agent owing to the difference in inherent excitation wavelengths. Particularly, the single NIR light (660 nm)-triggered PTT and PDT nanoplatform, constructed from chlorin e6 (Ce6) and copper sulfide (CuS) nanoparticles (NPs), has never been reported. Herein, we, for the first time, designed and established a dual-modal phototherapeutic nanoplatform that achieved both PTT and PDT under single NIR laser (660 nm) irradiation for Ce6 and CuS NPs with the strategy of core-shell structured CuS@Carbon integrated with Ce6. Introducing of carbon shell not only endows small CuS NPs with excellent tumor accumulation, but also significantly strengthens the photothermal performance of CuS NPs, realizing efficient photothermal performance under 660 nm laser irradiation. Moreover, Ce6 in carbon shell endowed the nanoplatform with photodynamic effect under 660 nm laser irradiation. The as-prepared Ce6/CuS@Carbon nanoplatform thus achieved dual-modal phototherapy under single NIR laser irradiation, significantly inhibiting tumor growth with minimal adverse effects and superior biosafety.

Concept Design, Development and Preliminary Physical and Chemical Characterization of Tamoxifen-Guided-Mesoporous Silica Nanoparticles.

Conventional chemotherapies used for breast cancer (BC) treatment are non-selective, attacking both healthy and cancerous cells. Therefore, new technologies that enhance drug efficacy and ameliorate the off-target toxic effects exhibited by currently used anticancer drugs are urgently needed. Here we report the design and synthesis of novel mesoporous silica nanoparticles (MSNs) equipped with the hormonal drug tamoxifen (TAM) to facilitate guidance towards estrogen receptors (ERs) which are upregulated in breast tumours. TAM is linked to the MSNs using a poly-ʟ-histidine (PLH) polymer as a pH-sensitive gatekeeper, to ensure efficient delivery of encapsulated materials within the pores. XRD, HR-TEM, DLS, SEM, FT-IR and BET techniques were used to confirm the successful fabrication of MSNs. The MSNs have a high surface area (>1000 m2/g); and a mean particle size of 150 nm, which is an appropriate size to allow the penetration of premature blood vessels surrounding breast tumours. Successful surface functionalization was supported by FT-IR, XPS and TGA techniques, with a grafting ratio of approximately 29%. The outcomes of this preliminary work could be used as practical building blocks towards future formulations.

Development and In Vitro Evaluation of 5-Fluorouracil-Eluting Stents for the Treatment of Colorectal Cancer and Cancer-Related Obstruction.

Self-expanding metal stents (SEMSs) are currently the gold standard for the localised management of malignant gastrointestinal (GI) stenosis and/or obstructions. Despite encouraging clinical success, in-stent restenosis caused by tumour growth is a significant challenge. Incorporating chemotherapeutic drugs into GI stents is an emerging strategy to provide localised and sustained release of drugs to intestinal malignant tissues to prevent tumour growth. Therefore, the aim of this work was to develop and evaluate a local GI stent-based delivery system that provides a controlled release of 5-fluorouracil (5FU) over a course of several weeks to months, for the treatment of colorectal cancer and cancer-related stenosis/obstructions. The 5FU-loaded GI stents were fabricated via sequential dip-coating of commercial GI stents with a drug-loaded polyurethane (PU) basecoat and a drug-free poly(ethylene-co-vinyl acetate) (PEVA) topcoat. For comparison, two types of commercial stents were investigated, including bare and silicone (Si) membrane-covered stents. The physicochemical properties of the 5FU-loaded stents were evaluated using photoacoustic Fourier-transform infrared (PA-FTIR) spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and thermal analysis. In vitro release studies in biological medium revealed that the 5FU-loaded stents provided a sustained release of drug over the period studied (18 d), and cell viability, cell cycle distribution and apoptosis assays showed that the released 5FU had comparable anticancer activity against human colon cancer cells (HCT-116) to pure 5FU. This study demonstrates that dip-coating is a facile and reliable approach for fabricating drug-eluting stents (DESs) that are promising candidates for the treatment of GI obstructions and/or restenosis.

Quality-by-Design Approach for the Development of Nano-Sized Tea Tree Oil Formulation-Impregnated Biocompatible Gel with Antimicrobial Properties.

Despite the promising properties of tea tree oil (TTO) as potential therapeutics for several superficial skin conditions, certain limitations such as physical instability and skin irritation have restricted its widespread use. This study focuses on developing a rationally designed lipid-based nanoformulation (TTO-LNF) in accordance with the US Food and Drug Administration standard using a well-recognized quality-by-design (QbD) approach. Using a mixture experimental design, TTO-LNF has been optimized with 5% TTO, 10% surfactant, 5% co-surfactant, and 80% water, which showed a 14.4 ± 4.4 nm droplet size and 0.03 ± 0.01 polydispersity index (PDI). To ease the topical administration, the TTO-LNF gel formulation was further developed using xanthan gum to achieve the desired viscosity and form a gel. The in vitro antibacterial tests of TTO-LNF showed promising inhibitory effects toward both Gram-negative and Gram-positive bacteria. In fact, a complete growth inhibition of S. epidermidis was observed when exposed to TTO-LNF and TTO-LNF gel for 24 h, showing better activity than antibiotic kanamycin (25 µg/mL). Additionally, the in vitro release study showed a sustained release profile with a 50% release in 24 h, which could be beneficial to reduce the toxicity and thereby improve the therapeutic efficacy for long-acting applications. Furthermore, the formulations were remarkably stable at 40 °C/75% Relative humidity (RH) for at least 4 weeks. Therefore, this study presents a promising strategy to develop a biocompatible and stable formulation that can be used for the topical treatment of skin infections.

Three-dimensional printed 5-fluorouracil eluting polyurethane stents for the treatment of oesophageal cancers.

Oesophageal stents have been widely used to prevent occlusion or stenosis in the treatment of oesophageal cancers. However, stent restenosis caused by tumour ingrowth occurs frequently after stent placement. Incorporating anti-cancer drugs into endoluminal stents is a promising strategy to provide a sustained release of drugs to oesophageal malignant tissues while prolonging the retention of the stent and relieving dysphagia. Recognizing the potential of 3D printing to produce personalised stents with patient specific geometries, we herein report the development of a drug-loaded 3D printed stent for the sustained local delivery of 5-fluorouracil (5-FU) to treat oesophageal cancer. The 3D printed drug-eluting stents (DESs) were fabricated via fused deposition modelling using 5-FU-loaded polyurethane filament. Determination of the 5-FU in the filament and stent (>97%) confirmed that minimal degradation of the drug occurred during the thermal extrusion and 3D printing processes. The physicochemical properties of the stents were investigated using photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and mechanical testing. In vitro release studies revealed that the drug-loaded stents provided a sustained release of 5-FU over a period of 110 days and allowed the constant diffusion of 5-FU when in contact with oesophageal mucosa. Furthermore, the 3D printed stents exhibited good stability following sterilization with gamma or UV irradiation, and during accelerated storage. This study demonstrates that 3D printing is a powerful tool for manufacturing DESs which could easily be customized to provide personalized, patient specific geometries and drug doses.

Influence of Polymer Composition on the Controlled Release of Docetaxel: A Comparison of Non-Degradable Polymer Films for Oesophageal Drug-Eluting Stents.

Following the huge clinical success of drug-eluting vascular stents, there is a significant interest in the development of drug-eluting stents for other applications, such as the treatment of gastrointestinal (GI) cancers. Central to this process is understanding how particular drugs are released from stent coatings, which to a large extent is controlled by drug-polymer interactions. Therefore, in this study we investigated the release of docetaxel (DTX) from a selection of non-degradable polymer films. DTX-polymer films were prepared at various loadings (1, 5 and 10% w/w) using three commercially available polymers including poly(dimethylsiloxane) (PSi), poly (ethylene-co-vinyl acetate) (PEVA) and Chronosil polyurethane (PU). The formulations were characterised using different techniques such as photoacoustic Fourier-transform infrared (PA-FTIR) spectrophotometry, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The effect of DTX on the mechanical properties of the films, in-vitro release, and degradation tests were also assessed. For all polymers and DTX loadings, the drug was found to disperse homogenously without crystallisation within the polymer matrix. While no specific interactions were observed between DTX and PSi or PEVA, hydrogen-bonding appeared to be present between DTX and PU, which resulted in a concentration-dependent decrease in the Young's moduli of the films due to disruption of inter-polymeric molecular interactions. In addition, the DTX-PU interactions were found to modulate drug release, providing near-linear release over 30 days, which was accompanied by a significant reduction in degradation products. The results indicate that DTX-loaded PU films are excellent candidates for drug-eluting stents for the treatment of oesophageal cancer.

Novel Tamoxifen Nanoformulations for Improving Breast Cancer Treatment: Old Wine in New Bottles.

Breast cancer (BC) is one of the leading causes of death from cancer in women; second only to lung cancer. Tamoxifen (TAM) is a hydrophobic anticancer agent and a selective estrogen modulator (SERM), approved by the FDA for hormone therapy of BC. Despite having striking efficacy in BC therapy, concerns regarding the dose-dependent carcinogenicity of TAM still persist, restricting its therapeutic applications. Nanotechnology has emerged as one of the most important strategies to solve the issue of TAM toxicity, owing to the ability of nano-enabled-formulations to deliver smaller concentrations of TAM to cancer cells, over a longer period of time. Various TAM-containing-nanosystems have been successfully fabricated to selectively deliver TAM to specific molecular targets found on tumour membranes, reducing unwanted toxic effects. This review begins with an outline of breast cancer, the current treatment options and a history of how TAM has been used as a combatant of BC. A detailed discussion of various nanoformulation strategies used to deliver lower doses of TAM selectively to breast tumours will then follow. Finally, a commentary on future perspectives of TAM being employed as a targeting vector, to guide the delivery of other therapeutic and diagnostic agents selectively to breast tumours will be presented.

Doxorubicin-Loaded Delta Inulin Conjugates for Controlled and Targeted Drug Delivery: Development, Characterization, and In Vitro Evaluation.

Delta inulin, also known as microparticulate inulin (MPI), was modified by covalently attaching doxorubicin to its nanostructured surface for use as a targeted drug delivery vehicle. MPI is readily endocytosed by monocytes, macrophages, and dendritic cells and in this study, we sought to utilize this property to develop a system to target anti-cancer drugs to lymphoid organs. We investigated, therefore, whether MPI could be used as a vehicle to deliver doxorubicin selectively, thereby reducing the toxicity of this antibiotic anthracycline drug. Doxorubicin was covalently attached to the surface of MPI using an acid-labile linkage to enable pH-controlled release. The MPI-doxorubicin conjugate was characterized using FTIR and SEM, confirming covalent attachment and indicating doxorubicin coupling had no obvious impact on the physical nanostructure, integrity, and cellular uptake of the MPI particles. To simulate the stability of the MPI-doxorubicin in vivo, it was stored in artificial lysosomal fluid (ALF, pH 4.5). Although the MPI-doxorubicin particles were still visible after 165 days in ALF, 53% of glycosidic bonds in the inulin particles were hydrolyzed within 12 days in ALF, reflected by the release of free glucose into solution. By contrast, the fructosidic bonds were much more stable. Drug release studies of the MPI-doxorubicin in vitro, demonstrated a successful pH-dependent controlled release effect. Confocal laser scanning microscopy studies and flow cytometric analysis confirmed that when incubated with live cells, MPI-doxorubicin was efficiently internalized by immune cells. An assay of cell metabolic activity demonstrated that the MPI carrier alone had no toxic effects on RAW 264.7 murine monocyte/macrophage-like cells, but exhibited anti-cancer effects against HCT116 human colon cancer cells. MPI-doxorubicin had a greater anti-cancer cell effect than free doxorubicin, particularly when at lower concentrations, suggesting a drug-sparing effect. This study establishes that MPI can be successfully modified with doxorubicin for chemotherapeutic drug delivery.

Preparation and Characterization of Oxidized Inulin Hydrogel for Controlled Drug Delivery.

Inulin-based hydrogels are useful carriers for the delivery of drugs in the colon-targeted system and in other biomedical applications. In this project, inulin hydrogels were fabricated by crosslinking oxidized inulin with adipic acid dihydrazide (AAD) without the use of a catalyst or initiator. The physicochemical properties of the obtained hydrogels were further characterized using different techniques, such as swelling experiments, in vitro drug release, degradation, and biocompatibility tests. The crosslinking was confirmed with Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), and differential scanning calorimetry (DSC). In vitro releases of 5-fluorouracil (5FU) from the various inulin hydrogels was enhanced in acidic conditions (pH 5) compared with physiological pH (pH 7.4). In addition, blank gels did not show any appreciable cytotoxicity, whereas 5FU-loaded hydrogels demonstrated efficacy against HCT116 colon cancer cells, which further confirms the potential use of these delivery platforms for direct targeting of 5-FU to the colon.