Local drug presentation made possible by drug-eluting depots provides benefits for a vast array of diseases, including cancer, microbial infection, and wound healing. Drug-eluting depots provide sustained drug release of therapeutics directly at disease sites with tunable kinetics, remove the need for drugs to access disease sites from circulation, and reduce the side effects associated with systemic therapy. Recently, we introduced an entirely novel approach to local drug presentation named Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs enables local drug presentation without any material carriers, capitalizing on innate tissue structures to anchor drugs at the site of administration.

In this report, we comprehensively evaluate the local and systemic toxicological profile of a paclitaxel version of TRAPs in mice by clinical observations, body weight monitoring, histopathological evaluations of injection sites and major organs, as well as blood and urine analyses.

We find that intradermal administration of TRAP-paclitaxel does not induce substantial toxic effects. Localized inflammatory responses were observed at the injection sites and secondary minimal, non-specific inflammation was observed in the liver. All other organs displayed unremarkable histological findings.

These findings support the potential of TRAP-paclitaxel as a promising candidate for localized cancer treatment, offering high-concentration drug delivery while mitigating scarring and adverse side effects.

Implant-based breast reconstruction is associated with increased risk of early infection and late-stage capsular contracture.

We evaluated the feasibility of a dual drug-releasing patch that enabled the controlled delivery of antibiotics and immunosuppressants in a temporally and spatially appropriate manner to the implant site.

The efficacy of a dual drug-releasing patch, which was 3-dimensional-printed (3D-printed) with tissue-derived biomaterial ink, was evaluated in rats with silicone implants. The groups included implant only (n = 10); implant plus bacterial inoculation (n = 14); implant, bacterial inoculation, and patch loaded with gentamycin placed on the ventral side of the implant (n = 10), and implant, bacterial inoculation, and patch loaded with gentamycin and triamcinolone acetonide (n = 9). Histologic and immunohistochemical analyses were performed 8 weeks after implantation.

The 2 drugs were sequentially released from the dual drug-releasing patch and exhibited different release profiles. Compared to the animals with bacterial inoculation, those with the antibiotic-only and the dual drug-releasing patch exhibited thinner capsules and lower myofibroblast activity and inflammation, indicating better tissue integration and less foreign body response. These effects were more pronounced with the dual drug-releasing patch than with the antibiotic-only patch.

The 3D-printed dual drug-releasing patch effectively reduced inflammation and capsule formation in a rat model of silicone breast reconstruction. The beneficial effect of the dual drug-releasing patch was better than that of the antibiotic-only patch, indicating its therapeutic potential as a novel approach to preventing capsular contracture while reducing concerns of systemic side effects.

Flavonoids may help ameliorate the incidence of the major causes of tumor-related mortality, such as pancreatic ductal adenocarcinoma (PDAC) and lung cancer, which are predicted to steadily increase between 2020 to 2030. Here we compared the effect of chrysin and chrysin nanoparticles (CCNPs) with 5-fluorouracil (5-FLU) on the activity and expression of mitochondrial complex II (CII) to induce apoptosis in pancreatic (PANC-1) and lung (A549) cancer cells.

Chrysin nanoparticles (CCNPs) were synthesized and characterized, and the IC₅₀ was evaluated in normal, PANC-1, and A549 cell lines using the MTT assay. The effect of chrysin and CCNPs on CΙΙ activity, superoxide dismutase activity, and mitochondria swelling were evaluated. Apoptosis was assessed using flow cytometry, and expression of the C and D subunits of SDH, sirtuin-3 (SIRT-3), and hypoxia-inducible factor (HIF-1α) was evaluated using RT-qPCR.

The IC₅₀ of CII subunit C and D binding to chrysin was determined and used to evaluate the effectiveness of treatment on the activity of SDH with ubiquinone oxidoreductase. Enzyme activity was significantly decreased (chrysin < CCNPs < 5-FLU and CCNPs < chrysin < 5-FLU, respectively), which was confirmed by the significant decrease of expression of SDH C and D, SIRT-3, and HIF-1α mRNA (CCNPs < chrysin < 5-FLU). There was also a significant increase in the apoptotic effects (CCNPs > chrysin > 5-FLU) in both PANC-1 and A549 cells and a significant increase in mitochondria swelling (CCNPs < chrysin < 5-FLU and CCNPs > chrysin > 5-FLU, respectively) than that in non-cancerous cells.

Treatment with CCNPs improved the effect of chrysin on succinate-ubiquinone oxidoreductase activity and expression and therefore has the potential as a more efficient formulation than chemotherapy to prevent metastasis and angiogenesis by targeting HIF-1α in PDAC and lung cancer.

Post-surgical chemotherapy in pancreatic cancer has notorious side effects due to the high dose required. Multiple devices have been designed to tackle this aspect and achieve a delayed drug release. This study aimed to explore the controlled and sustained local delivery of a reduced drug dose from an irinotecan-loaded electrospun nanofiber membrane (named TARTESSUS) that can be placed on the patients' tissue after tumor resection surgery. The drug delivery system formulation was made of polycaprolactone (PCL). The mechanical properties and the release kinetics of the drug were adjusted by the electrospinning parameters and by the polymer ratio between 10 w.t.% and 14 w.t.% of PCL in formic acid:acetic acid:chloroform (47.5:47.5:5). The irinotecan release analysis was performed and three different release periods were obtained, depending on the concentration of the polymer in the dissolution. The TARTESSUS device was tested in 2D and 3D cell cultures and it demonstrated a decrease in cell viability in 2D culture between 72 h and day 7 from the start of treatment. In 3D culture, a decrease in viability was seen between 72 h, day 7 (p < 0.001), day 10 (p < 0.001), 14 (p < 0.001), and day 17 (p = 0.003) as well as a decrease in proliferation between 72 h and day 10 (p = 0.030) and a reduction in spheroid size during days 10 (p = 0.001), 14 (p < 0.001), and 17 (p < 0.001). In conclusion, TARTESSUS showed a successful encapsulation of a chemotherapeutic drug and a sustained and delayed release with an adjustable releasing period to optimize the therapeutic effect in pancreatic cancer treatment.

Three-dimensional (3D) printing technology involves the application of digital models to create 3D objects. It is used in construction and manufacturing and has gradually spread to medical applications, such as implants, drug development, medical devices, prosthetic limbs, and in vitro models. The application of 3D printing has great prospects for development in orthopedics, maxillofacial plastic surgery, cardiovascular conditions, liver disease, and other fields. With in-depth research on 3D printing technology and the continuous update of printing materials, this technology also shows broad development prospects in renal medicine. In this paper, the author mainly summarizes the basic theory of 3D printing technology, its research progress, application status, and development prospect in renal diseases.

The prognosis of gastric cancer in an advanced stage remains poor. The exact efficacy of the use of intraoperative sustained-release chemotherapy with 5-fluorouracil (5-FU) in advanced-stage gastric cancer is still unelucidated.

To explore the long-term survival benefit of using sustained-release 5-FU implants in stage II and stage III gastric cancer patients.

Patients with gastric cancer in a locally advanced stage and who underwent an R0 radical resection between Jan 2014, to Dec 2016, in this single institution were included. Patients with pathological diagnoses other than adenocarcinoma were excluded. All included patients were grouped according to whether intraoperative sustained-release (SR) chemotherapy with 5-FU was used or not (NSR). The primary end-point was 5-year overall survival. Kaplan-Meier method with log-rank test was used to analyze the overall survival of patients and Cox analysis was used to analyze prognosis factors of these patients.

In total, there were 563 patients with gastric cancer with locally advanced stage, who underwent an R0 radical resection. 309 patients were included in the final analysis. 219 (70.9%) were men, with an average age of 58.25 years. Furthermore, 56 (18.1%) received neoadjuvant chemotherapy, and 191 (61.8%) were in TNM stage III. In addition, 158 patients received intraoperative sustained-release chemotherapy with 5-FU and were included in the SR group, while the other 161 patients were included in the NSR group. The overall complication rate was 12.94% in the whole group and 10.81%, 16.46% in SR and NSR groups, respectively. There were no significant differences between the two groups in overall survival and complication rate (P > 0.05). The multivariate cox analysis indicated that only N Stage and neoadjuvant therapy were independent influencing factors of survival.

Intraoperative sustained-release chemotherapy usage with 5-FU, did not improve the survival of patients who underwent an R0 radical resection in locally advanced stage of gastric cancer.

We investigated the anticancer effect of the aptamer-conjugated gemcitabine-loaded atelocollagen patch in a pancreatic cancer patient-derived xenograft (PDX) model to propose a future potential adjuvant surgical strategy during curative pancreatic resection for pancreatic cancer. A pancreatic cancer PDX model was established. Animals were grouped randomly into a no-treatment control group; treatment group treated with intraperitoneal gemcitabine injection (IP-GEM) or aptamer-conjugated gemcitabine (APT:GEM); and transplant with three kinds of patches: atelocollagen-aptamer-gemcitabine (patch I), atelocollagen-inactive aptamer-gemcitabine (patch II), and atelocollagen-gemcitabine (patch III). Tumor volumes and response were evaluated based on histological analysis by H&E staining and Immunohistochemistry (IHC) was performed. Anticancer therapy-related toxicity was evaluated by hematologic findings. The patch I group showed the most significant reduction of tumor growth rate, compared with the no-treatment group (p < 0.05). However, other treatment groups were not found to show significant reduction in tumor growth rate (0.05 < p < 0.1). There was no microscopic evidence suggesting potential toxicity, such as inflammation, nor necrotic changes in liver, lung, kidney, and spleen tissue. In addition, no leukopenia, anemia, or neutropenia was observed in the patch I group. This implantable aptamer-drug conjugate system is thought to be a new surgical strategy to augment the oncologic significance of margin-negative resection in treating pancreatic cancer in near future.

Three-dimensional printing (3DP) technology is an innovative tool used in manufacturing medical devices, producing alloys, replacing biological tissues, producing customized dosage forms and so on. Stereolithography (SLA), a 3D printing technique, is very rapid and highly accurate and produces finished products of uniform quality. 3D formulations have been optimized with a perfect tool of artificial intelligence learning techniques. Complex designs/shapes can be fabricated through SLA using the photopolymerization principle. Different 3DP technologies are introduced and the most promising of these, SLA, and its commercial applications, are focused on. The high speed and effectiveness of SLA are highlighted. The working principle of SLA, the materials used and applications of the technique in a wide range of different sectors are highlighted in this review. An innovative idea of 3D printing customized pharmaceutical dosage forms is also presented. SLA compromises several advantages over other methods, such as cost effectiveness, controlled integrity of materials and greater speed. The development of SLA has allowed the development of printed pharmaceutical devices. Considering the present trends, it is expected that SLA will be used along with conventional methods of manufacturing of 3D model. This 3D printing technology may be utilized as a novel tool for delivering drugs on demand. This review will be useful for researchers working on 3D printing technologies.

5-Fluorouracil (5-FU) is a "cytotoxic" drug used for cancer chemotherapy, which inhibits cells division via affecting DNA synthesis. Although being widely used for cancer treatment, 5-FU has non-negligible side effects. In the present study, the effects of 5-FU on oocyte and early embryonic development were investigated. Multiple intraperitoneal administration of 5-FU (50 mg/kg/day) in female mice resulted in small ovarian size and reduced number of corpus luteum in the ovary, and lead to ovulation failure. However, these defects could be recovered after one week. In vitro experiments further indicated that exposure to 5-FU inhibited oocytes maturation and reduced developmental potential of pre-implantation embryos. Our data suggested that 5-FU has negative impact on ovarian function, oocyte and early embryonic development, but the adverse effect could be reversed after withdrawal of 5-FU administration.

The objective of this study was to investigate the pattern and the oncologic impact of local recurrence after surgical resection of pancreatic cancer.

From July 1992 to December 2016, 388 patients who underwent curative-intent surgery for pancreatic ductal adenocarcinoma were retrospectively reviewed.

At a median follow-up of 29.0 months, 286 (73.7%) of the 367 patients experienced recurrence, and the 5-year overall survival rate was 31.3%. The first recurrence pattern was local in 83 patients (22.0%), systemic in 152 patients (40.2%), and locosystemic in 51 patients (13.5%). There was no difference in overall survival between the patients who had either local or systemic recurrence (P > 0.05). Remnant pancreas, common hepatic artery, celiac trunk, and para-aortic area were the common local recurrence sites in both head and body/tail cancer. However, the superior mesenteric artery (P = 0.050) and portal vein (P = 0.001) were more frequent local recurrence sites for a head tumor, and the surgical bed was a common recurrence site for body/tail tumor (P < 0.001).

Our study shows the importance of local recurrence on overall survival and that preferred sites of local recurrence according to tumor location are predictable.

Relapse, metastasis, and chemo-resistance are the main factors responsible for the failure of surgical treatment of malignant tumors, and typically are the main obstacles to effective cancer treatment. Although significant advances have been made in the field of cancer chemotherapy, many patients still receive inadequate treatment due to the severe adverse effects of these drugs, resulting in an inability to reach therapeutic concentrations at the tumor site with systemic chemotherapy. Thus, a biological patch loaded with chemotherapeutic drugs could be an ideal strategy for the treatment of cancer at the tumor site.

We developed an acellular matrix using the submucosa of porcine jejunum, then loaded this matrix with different amounts of 5-fluorouracil (5-FU) and rapamycin nanoparticles. Cell proliferation and apoptosis were analyzed by flow cytometry and related markers were evaluated using real-time PCR and western blotting. The patches were evaluated in vitro to characterize their release kinetics and therapeutic feasibility. We then analyzed the therapeutic efficacy and systemic toxicity of these patches in vivo by using them in a mouse model of colon cancer.

The patches delivered 5-FU and rapamycin in a controlled manner for more than 8 weeks, arrested the cell cycle of LoVo cells and sw480 cells at G2/M phase, and induced apoptosis in vitro. The patches also suppressed the growth of xenografted tumors in vivo with lower adverse effects than typically observed with systemic administration of these drugs.

We demonstrated that patches loaded with 5-FU-RAPA-PLA-NP significantly inhibited the growth of colon cancer in vitro and in vivo. These results demonstrated the feasibility of the use of a multi-effect biological patch for cancer treatment.

Pancreatic cancer (PanCa) is a major cause of cancer-related death due to limited therapeutic options. As pancreatic tumors are highly desmoplastic, they prevent appropriate uptake of therapeutic payloads. Thus, our objective is to develop a next-generation nanoparticle system for treating PanCa. We generated a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PPNPs). This formulation exhibited optimal size (~160 nm) and negative Zeta potential (-6.02 mV), efficient lipid raft mediated internalization, pronounced inhibition in growth and metastasis in vitro, and in chemo-naïve and chemo-exposed orthotopic xenograft mouse models. Additionally, PPNPs altered nanomechanical properties of PanCa cells as suggested by the increased elastic modulus in nanoindentation analyses. Immunohistochemistry of orthotopic tumors demonstrated decreased expression of tumorigenic and metastasis associated proteins (ki67, vimentin and slug) in PPNPs treated mice. These results suggest that PPNPs represent a viable and robust platform for (PanCa).

Actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS) are precursor lesions for cutaneous squamous cell carcinoma (cSCC), the second most common form of cancer. Current topical therapies for AKs and SCCIS promote skin inflammation to eradicate lesions and do not directly target the biological mechanisms driving growth. We hypothesized that topical small molecule inhibitors targeting kinases promoting keratinocyte growth in AKs and SCCIS could induce regression of these lesions with less inflammation. To test this hypothesis, we determined the efficacy of topical dasatinib, 5-fluorouracil and BEZ-235 in inducing regression of cSCCs in the K14-Fyn Y528 transgenic mouse model. Topical dasatinib induced regression of cSCC with less inflammation, no ulceration and no mortality compared to 5-fluorouracil. Topical BEZ-235 induced cSCC regression similar to dasatinib without erythema or ulceration. These data indicate that topical small molecule kinase inhibitors targeting drivers of AK/SCCIS/cSCC growth represent a promising therapeutic approach to treat these common skin lesions.

Epilepsy is a chronic brain disease characterized by unprovoked seizures, which can have severe consequences including loss of awareness and death. Currently, 30% of epileptic patients do not receive adequate seizure alleviation from oral routes of medication. Over the last decade, local drug delivery to the focal area of the brain where the seizure originates has emerged as a potential alternative and may be achieved through the fabrication of drug-loaded polymeric implants for controlled on-site delivery.

This review presents an overview of the latest advanced fabrication techniques for controlled drug delivery systems for refractory epilepsy treatment. Recent advances in the different techniques are highlighted and the limitations of the respective techniques are discussed.

Advances in biofabrication technologies are expected to enable a new paradigm of local drug delivery systems through offering high versatility in controlling drug release profiles, personalized customization and multi-drug incorporation. Tackling some of the current issues with advanced fabrication methods, including adhering to GMP-standards and industrial scale-up, together with innovative solutions for complex designs will see to the maturation of these techniques and result in increased clinical research into implant-based epilepsy treatment.

GMP: Good manufacturing process; DDS(s): Drug delivery system(s); 3D: Three-dimensional; AEDs: Anti-epileptic drugs; BBB: Blood brain barrier; PLA: Polylactic acid; PLGA: Poly(lactic-co-glycolic acid); PCL: poly(ɛ-caprolactone); ESE: Emulsification solvent evaporation; O/W: Oil-in-water; W/O/W: Water-in-oil-in-water; DZP: Diazepam; PHT: Phenytoin; PHBV: Poly(hydroxybutyrate-hydroxyvalerate); PEG: Polyethylene glycol; SWD: Spike-and-wave discharges; CAD: Computer aided design; FDM: Fused deposition modeling; ABS: Acrylonitrile butadiene styren; eEVA: Ethylene-vinyl acetate; GelMA: Gelatin methacrylate; PVA: Poly-vinyl alcohol; PDMS: Polydimethylsiloxane; SLA: Stereolithography; SLS: Selective laser sintering.

Pancreatic cancer has a high rate of local recurrence and poor prognosis even with adjuvant chemotherapy after curative resection. The aim of this study was to investigate if local drug delivery combined with low dose systemic chemotherapy can increase the therapeutic effect of chemotherapy while reducing systemic toxicities. Poly-L-lactic acid-based 5-FU releasing patch was fabricated by electrospinning, and its tumour killing effects were first confirmed in vitro. The 5-FU patch directly adhered to the tumour in subcutaneous and orthotopic murine models, and induced a significant decrease in tumour size. Systemic gemcitabine treatment group, 5-FU drug releasing patch group, and systemic gemcitabine plus 5-FU patch group were compared by tumour size measurement, non-invasive bio-imaging, and histology in subcutaneous models. Combination of local drug patch and systemic chemotherapy led to increased tumour suppression effects that lasted longer, as well as increased survival rate. Histology revealed higher degree of apoptosis in the combined group. Systemic toxicity was recovered within 7 days after the treatment in all mice. Conclusively, local drug delivery using biocompatible polymer patch significantly inhibited tumour growth, and combination with systemic chemotherapy was more effective than single systemic chemotherapy.