A Retrospective Review of an Off-label Bromelain-based Selective Enzymatic Debridement (Nexobrid®) in the Treatment of Deep, Partial, and Full Thickness Burns and Hard to Heal Wounds.

BACKGROUND: Rapid and selective bromelain-based enzymatic debridement provides a non-surgical alternative for the eschar removal in deep burns, which allows for early debridement of large surface areas, accurate evaluation of burn and wound depth, and the need for skin grafting. OBJECTIVES: To evaluate the efficacy of application of a bromelain-based selective enzymatic debridement (Nexobrid®) beyond the manufacturer's guidelines for use in burns > 48 hours as well as chemical, electrical, and pediatric burns, and chronic wounds. METHODS: This retrospective review included records collected between January 2017 and April 2019, from male and female patients aged 8 months to 99 years with deep burns or wounds treated with bromelain-based selective enzymatic debridement. RESULTS: Of the 33 patients who received the bromelain-based selective enzymatic debridement agent beyond the manufacturer's guidelines, 25 (76%) were observed to have successful debridement of the eschar, 8 (24%) were observed to have little effect on the burn eschar. Sixteen required further surgery after debridement. Clinical data on the use of bromelain-based selective enzymatic debridement agents are limited, but these results suggest the capacity to effectively debride burns > 48 hours (late presentation burns), use for pediatrics and for chemical and electrical burns, and apply to hard to heal full thickness chronic wounds. CONCLUSIONS: Bromelain-based selective enzymatic debridement was found to be an effective treatment modality beyond the recommended guidelines including late presentation burns and chronic wounds. This debridement method warrants further consideration when making clinical decisions concerning burn and wound care.

[Enzymatic débridement as a treatment option for deep dermal burns of the hand]. / Enzymatisches Débridement als Therapieoption bei tiefdermalen Verbrennungen der Hand.

Burns and thermal injuries from other causes often affect exposed body regions such as the hands. Besides aesthetic aspects, deep dermal burns of the skin are often critical from a functional point of view, especially for important subcutaneous structures. This article reports the course of two patients who received enzymatic debridement with bromelain-based salve as a treatment for deep grade burns of the hands.

Instantaneous Specific Burn Debridement With an Enzymatic Debriding Agent: A New Resource for the Treatment of Burns.

Nexobrid is a new resource for debridement that has emerged in recent years and is gaining relevance in the treatment of all kinds of thermal injuries. This product is an ointment (formed with a mixture of pineapple-derived enzymes enriched with bromelain) that is directly applied over the burn. With a single application, it performs a burned tissue-specific debridement in less than 4 hr, leaving a vital and completely debrided wound bed. In this article, we describe our experience with this product, and through a representative case, we explain the management of these patients in our Burns unit in consonance with national and international consensus.

Treatment of Genital Burn Injuries: Traditional Procedures and New Techniques.

OBJECTIVE: Because genital burns are rare, only limited information on treatment guidelines is available in the literature. Vital tissue should be preserved to promote spontaneous healing because reconstruction does not always lead to satisfying results. The aim of this report is to present a general overview of current, prevailing treatment for genital burns and compare this to study authors' experiences. In addition, the article describes an entirely new approach of tissue-preserving bromelain-based enzymatic debridement of genital burn wounds. METHODS: This single-center study includes all patients who were treated for severe genital and perineal burn wounds at a burn intensive care unit between December 1995 and December 2016. A review of literature was performed in PubMed covering the years 1990 to 2016. RESULTS: A total of 149 patients were admitted with severe burns or scalding of the genitals or the perineum. As in the majority of cases reported in the current literature, most of these patients were treated conservatively. When there was demarcation of necrotic tissue, tangential excision and skin grafting were performed, and since 2015, 3 patients admitted to this facility have been treated with bromelain-based debridement followed by spontaneous healing. Certain small-scale studies in the literature describe a disproportionate number of surgical interventions. CONCLUSIONS: Based on this evidence, study authors support a conservative view of genital burn treatment. Enzymatic debridement allows earlier and more selective debridement, which can improve the aesthetic outcome.

Bromelain Loading and Release from a Hydrogel Formulated Using Alginate and Arabic Gum.

An ideal wound dressing ensures a moist environment around the wound area and absorbs exudates from the wound surface. Topical application of bromelain to incised wounds has been shown to reprogram the wound microenvironment to promote effective tissue repair. Combining the characteristics of hydrogels and bromelain is therefore of great interest. Herein, we describe the development of a hydrogel, formulated using alginate and Arabic gum, for bromelain loading and release. The hydrogel formulation was evaluated using response surface methodology, considering the pH value and the concentration of alginate and Arabic gum. Bromelain loading and release were evaluated based on passive diffusion. Differential scanning calorimetry and Fourier transform infrared spectroscopy were performed to confirm bromelain immobilization in the hydrogel. The final hydrogel formulation had a swelling ratio of 227 % and incorporated 19 % of bromelain from a bromelain solution. Bromelain immobilization in the hydrogel was the result of hydrogen bond formation and was optimal at 4 °C after 4 h of contact. This evidence suggests that bromelain entrapment into a hydrogel is a promising strategy for the development of wound dressings that support the debridement of burns and wounds.

Effect of Oral Administration of Bromelain on Postoperative Discomfort After Third Molar Surgery.

INTRODUCTION: The purpose of this prospective randomized controlled clinical trial was to evaluate the effect of oral administration of bromelain on discomfort after mandibular third molar surgery. MATERIALS AND METHODS: Eighty-four consecutive patients requiring surgical removal of a single mandibular impacted third molar under local anesthesia were randomly assigned to receiving no drug (control group, Group A), postoperative 40 mg bromelain every 6 hours for 6 days (Group B), preoperative 4 mg dexamethasone sodium phosphate as a submucosal injection (Group C), and preoperative 4 mg dexamethasone sodium phosphate as a submucosal injection plus postoperative 40 mg bromelain every 6 hours for 6 days (Group D). Standardized surgical and analgesic protocols were adopted. Maximum interincisal distance and facial contours were measured at baseline and on postoperative days 2 and 7. Pain was measured objectively by counting the number of analgesic tablets required. Patient perception of the severity of symptoms was assessed with a follow-up questionnaire (PoSSe scale). RESULTS: On postoperative day 2, there was a statistically significant reduction in facial edema in both Groups C and D compared with the control group, but no statistically significant differences were observed between Group B and the control group. At evaluation on postoperative day 7, Group D showed a statistically significant reduction in postoperative swelling compared with the control group. The combined use of bromelain and dexamethasone (Group D) induced a statistically significant reduction in the total number of analgesic tablets taken after surgery compared with the control group. The treatment groups had a limited, nonsignificant effect on trismus when compared with the control group. CONCLUSIONS: Bromelain used singly showed moderate anti-inflammatory efficacy, reducing postoperative swelling, albeit not to any significant extent compared with no drug administration. The combined use of bromelain and dexamethasone sodium phosphate yielded the best results in terms of control of postoperative discomfort.

[A 67-year old man with epigastric pain]. / 67-jähriger Patient mit epigastrischen Schmerzen.

A 67-year-old man suffering from epigastric pain showed a phytobezoar in the endoscopy. Therapy with Coca Cola® and enzymes was initiated. The (partial) lysis led to a migration of the bezoar into the ileum, resulting in a small bowel obstruction. After removal of the remaining bezoar via ileotomy a secondary pneumatosis intestinalis occurred. As a rare finding the (phyto-)bezoar should be considered as a differential diagnosis of abdominal pain - especially considering the rising numbers of bariatric surgery, which is a potential risk factor. Furthermore, intestinal obstruction after migration has to be considered as a relevant complication of treatment.

Perioperative Bromelain Therapy after Wisdom Teeth Extraction - A Randomized, Placebo-Controlled, Double-Blinded, Three-Armed, Cross-Over Dose-Finding Study.

Reduction in postoperative edema and inflammatory reactions is the key to the posttraumatic regeneration process. Use of bromelain is well established in this indication, but there is some controversy with regard to the optimal dosing of this drug. The aim of our study was therefore to investigate the efficacy of dosage-dependent therapy with bromelain in patients after wisdom teeth extraction by comparing the registered dosage 1000 FIP (Fédération Internationale Pharmaceutique) against higher dosages of 3000 FIP and 4500 FIP. A total of 75 patients were randomized to one of the three dosage arms, and 68 of these patients were finally analyzed in the modified intention-to-treat population. Patients involved underwent two surgery sessions: one study period being conducted under treatment with bromelain and the other with placebo. Postoperative swelling determined by a 3D face scanning system was defined as the primary endpoint; further efficacy parameters were maximum swelling, pain, difficulty in swallowing, and use of analgesics. A superiority of treatment with 3000 FIP and 4500 FIP versus 1000 FIP could not be demonstrated. The analysis of pooled bromelain treatments versus placebo did, however, show a clear trend in favor of bromelain for all assessments. Adverse events did not occur more frequently under bromelain therapy compared with placebo. This study thus clearly supports the clinical relevance of treatment of postoperative conditions with bromelain, and the recommended daily dose was sufficiently effective in this trial and indication. Copyright © 2016 John Wiley & Sons, Ltd.

Serenoa repens associated with selenium and lycopene extract and bromelain and methylsulfonylmethane extract are able to improve the efficacy of levofloxacin in chronic bacterial prostatitis patients.

OBJECTIVE: To date, the management of patients with chronic bacterial prostatitis (CBP) is not satisfactory, especially in terms of symptoms relief. Here, we evaluated the efficacy and the safety of a combination of serenoa repens, selenium and lycopene extract + bromelain and methylsulfonylmethane extract associated with levofloxacin in patients with CBP. MATERIALS AND METHODS: All patients with clinical and instrumental diagnosis of CBP, admitted to a single Urological Institution from March to June 2015 were enrolled in this phase III study. All enrolled patients were randomized into two groups: Group A received levofloxacin 500 mg o.d. for 14 days associated with lycopene and methylsulfonylmethane; Group B received levofloxacin (500 mg o.d. for 14 days) only. Clinical and microbiological analyses were carried out at the time of admission (T0) and during the followups at 1 month (T1) and 6 months (T2) from the end of the treatment. NIH Chronic Prostatitis Symptom Index (CPSI), International Prostatic Symptom Score (IPSS) and Quality of Well-Being (QoL) questionnaires were used. The main outcome measures were the rate of microbiological cure and the improvement in questionnaire results from baseline at the end of the follow-ups period. RESULTS: Forty patients were enrolled in Group A and 39 in Group B. During the follow-up (T1), we recorded a significant changes in terms of NIH-CPSI and IPSS in Group A (mean difference: 17.6 ± 2.65; 12.2 ± 2.33; p < 0.01; p < 0.05, respectively) and versus Group B at the intergroup analysis (mean difference: -9 ± 1.82; -8.33 ± 1.71; p < 0.05; p < 0.05, respectively). No differences were reported in terms of microbiological findings between the two groups. At the second follow-up visit (T2), questionnaire results demonstrated statistically significant differences between groups (p < 0.001). One patient in Group A (2.5%) and 7 patients (17.9%) in Group B showed a symptomatic and microbiological recurrence (p = 0.02). CONCLUSIONS: The combination of serenoa repens, selenium, lycopene + bromelain and methylsulfonylmethane extracts improved the clinical efficacy of levofloxacin in patients affected by CBP without the development of side effects.

[REVIEW OF 30 YEARS OF RESEARCH AND DEVELOPMENT OF AN ENZYMATIC DEBRIDEMENT AGENT FOR BURNS].

INTRODUCTION: Early removal of burn eschar is a cornerstone of burn care. The most commonly practiced eschar removal technique for deep burns in modern burn care is surgical debridement but this technique is associated with surgical burden and leads to unnecessary excision of viable tissue. GOALS: To review 30 years of research and development of an enzymatic debridement agent for burns. METHODS: Studies performed during the last 30 years are reviewed in this manuscript. RESULTS: Patients who underwent enzymatic debridement had a significantly shorter time to complete debridement, the surgical burden was significantly lower, hand burns did not necessitate escharotomy, and the long term results were favorable. DISCUSSION: Early enzymatic debridement leads to an efficient debridement, preservation of viable tissue, a reduction in surgical burden and favorable long term results. CONCLUSION: We believe early enzymatic debridement will lead to better care for burn victims and perhaps, even to a paradigm shift in the treatment of burns.

Poly(N-Isopropylacrylamide)-co-Acrylamide Hydrogels for the Controlled Release of Bromelain from Agroindustrial Residues of Ananas comosus.

This works reports the purification of bromelain extracted from Ananas comosus industrial residues by ethanol purification, its partial characterization from the crude extract as well as the ethanol purified enzyme, and its application onto poly(N-isopropylacrylamide)-co-acrylamide hydrogels. Bromelain was recovered within the 30-70 % ethanol fraction, which achieved a purification factor of 3.12-fold, and yielded more than 90 % of its initial activity. The resulting purified bromelain contained more than 360 U · mg(-1), with a maximum working temperature of 60 °C and pH of 8.0. Poly(N-isopropylacrylamide)-co-acrylamide hydrogels presented a swelling rate of 125 %, which was capable of loading 56 % of bromelain from the solution, and was able to release up to 91 % of the retained bromelain. Ethanol precipitation is suitable for bromelain recovery and application onto poly(N-isopropylacrylamide)-co-acrylamide hydrogels based on its processing time and the applied ethanol prices.

The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis.

To evaluate the efficacy of an association of N-acetyl cystein, alpha-lipoic acid, and bromelain (NAC/LA/Br) in the treatment of endometriosis we set up a new in vivo murine model. We explored the anti-inflammatory and proapoptotic effect of this combination on human endometriotic endothelial cells (EECs) and on endothelial cells isolated from normal uterus (UtMECs). We implanted fragments of human endometriotic cysts intraperitoneally into SCID mice to evaluate the efficacy of NAC/LA/Br treatment. UtMECs and EECs, untreated or treated with NAC/LA/Br, were activated with the proinflammatory stimulus TNF-α and their response in terms of VCAM1 expression was evaluated. The proapoptotic effect of higher doses of NAC/LA/Br on UtMECs and EECs was measured with a fluorogenic substrate for activated caspases 3 and 7. The preincubation of EECs with NAC/LA/Br prior to cell stimulation with TNF-α prevents the upregulation of the expression of the inflammatory "marker" VCAM1. Furthermore NAC/LA/Br were able to induce EEC, but not UtMEC, apoptosis. Finally, the novel mouse model allowed us to demonstrate that mice treated with NAC/LA/Br presented a lower number of cysts, smaller in size, compared to untreated mice. Our findings suggest that these dietary supplements may have potential therapeutic uses in the treatment of chronic inflammatory diseases like endometriosis.

Perioperative bromelain reduces pain and swelling and improves quality of life measures after mandibular third molar surgery: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: The purpose of the present study was to compare the effect of oral bromelain (4 × 250 mg) versus oral diclofenac sodium (4 × 25 mg) on pain, swelling, trismus, and quality of life (QOL) after surgical removal of impacted lower third molars. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study was planned. The sample included patients requiring extraction under local anesthesia of a single partial bony impacted mandibular third molar. The patients were randomly distributed into 1 of 3 groups: bromelain, diclofenac, and placebo. Treatment started 1 day before surgery and continued for 4 days. The predictor variable was the type of the drug given to the patients. The outcome variables were pain, swelling, and trismus, which were measured at 1, 3, and 7 days postoperatively. The other study variables included QOL measures to assess the patients' perception regarding the effect of surgery on their well-being and daily activities. A validated questionnaire was used to measure QOL. The data were analyzed using analysis of variance, multiple measures analysis of variance, or Pearson's χ(2) test, as appropriate. P < .05 was considered significant. RESULTS: A total of 45 subjects requiring surgical removal of a single impacted mandibular third molar under local anesthesia were included in the present study. The bromelain and diclofenac groups both showed a significant reduction in pain compared with the placebo group at all intervals (P < .05). Diclofenac also resulted in a significant reduction of swelling at 3 and 7 days, and bromelain resulted in an insignificant reduction. A nonsignificant reduction in trismus occurred in both treatment groups compared with the placebo group. Both treatment groups also showed a significant difference in the effect on QOL in most subscales and total scores (P < .05). The effect was comparable between the 2 treatment groups for all parameters and at all intervals. CONCLUSIONS: The results of our study have shown that oral bromelain is an effective therapy to improve the QOL after surgical removal of impacted lower third molars, with an effect on the postoperative sequelae comparable to that of preemptive diclofenac sodium.

Can dietary integrators provide a clinical benefit in the treatment of functional dyspepsia? results from a prospective study with TUBES Gastro.

AIM: Given the limited efficacy of conventional medical therapy for functional dyspepsia, patients frequently seek alternative medical approaches. The use of suc h alternative therapies has dramatically increased during the last decades. The scope of this prospective study was to provide evidence of the clinical benefit of the treatment of functional dyspepsia with a dietary integrator composed by sodium alginate, sodium bicarbonate, bromelin and essential oils. METHODS: This study enrolled a total of 100 patients affected by functional dyspepsia diagnosed primarily on the basis of typical symptoms and the exclusion of non-functional gastrointestinal diseases (negative upper gastrointestinaltract endoscopy and negative for H. pylori infections, including acid-related diseases), non-gastrointestinal diseases, and psychiatric illness. All patients enrolled were categorized in two symptom-predominant subgroups: dysmotility-like dyspepsia (N.=60) and reflux-like dyspepsia (N.=40). Patients were treated with TUBES Gastro (0.80 g oral tablets bid after main meals) for 4 weeks, on top of their current treatment with proton pump inhibitors or not. Efficacy was measured by a Numerical Rating Scale (NRS) at baseline and after 14 and 28 days of treatment with TUBES Gastro while safety and tolerability were evaluated based on the adverse event reporting from the patients. RESULTS: Sixty patients were diagnosed with dysmotility-like dyspepsia and were enrolled into the study; the majority was females (68%) with a mean age of 48.5 years (19-81). The mean baseline NRS score was 5.7 (4-8). A high statistically significant reduction of the NRS score was observed at 14 and 28 days: -1.5 (-26.3%) and -3.4 (-59.6%), respectively (P<0.0001). Forty patients were diagnosed with reflux-like dyspepsia and were enrolled into the study; the majority was males (70%) with a mean age of 49.1 years (24-80). The mean baseline NRS score was 6.8 (5-9). A high statistically significant reduction of the NRS score was observed at 14 and 28 days: -2.8 (-41.2%) and -4.8 (70.6%), respectively (P<0.0001). No side effects were collected during the study duration. CONCLUSION: The data obtained from this four-week study indicate that TUBES Gastro treatment was effective and well tolerated in reducing the symptomatology of patients affected by functional dysmotility-like and reflux-like dyspepsia.

[Impact of exogenous proteolytic enzymes on immunogenesis in patients with urogenital infections].

The use of systemic enzyme therapy in combination with antibiotics in the treatment of urogenital chlamydia infection in patients of both sexes proved to improve the therapeutic efficacy and to reduce the risk of the side effects.

Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19.

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed. RESULTS: BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg. CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.

Bromelain in the early phase of healing in acute crush Achilles tendon injury.

UNLABELLED: Bromelain, an enzyme extracted from the stem of the pineapple plant has been proposed as a treatment for reducing pain and swelling following acute muscle injuries but studies are yet to be done on its effect on tendon healing. This study therefore investigated the effects of bromelain on tenocyte proliferation and the tendon malondialdehyde (MDA) level in the early stage of healing in a crush injury to the Achilles tendon of Sprague-Dawley rats. Twenty four male rats were divided randomly into three groups; groups 2 and 3 had induced crush injury to the left Achilles tendon. Group 1; nil injury and nil treatment, Group 2; nil treatment, Group 3; oral bromelain treatment. Bromelain was given at a dosage of 7 mg/kg body weight daily over the first 14 days post-injury. On day 15 post injury, the animals were killed and the tendons excised and processed for histological study and MDA assay. The results showed a significant increase in the tenocyte population in the bromelain group; p < 0.05. There was, however, no significant difference in the MDA level. CONCLUSION: Based on this study, 600 GDU bromelain given once daily in acute tendon injury at a dosage of 7 mg/kg promoted healing by stimulating tenocyte proliferation.

A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer.

Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.

Halloysite nanotube-embedded microparticles for intestine-targeted co-delivery of biopharmaceuticals.

Microparticles (MPs) with pH-responding macropores have recently proved their significance for the delivery of vulnerable biomolecules for oral drug administration. The previous MP systems were proven to provide enhanced protection against the gastric environment, however, their application is hindered due to insufficient loading efficiencies and deficient penetration capabilities of encapsulated drugs across the mucus barrier. Here, we report a new co-delivery approach based on amine-functionalized halloysite nanotube (HNT)-embedded MPs (amine-HNT-MPs) with pH-responding macropores specifically designed to deal with the mucus barrier at the absorption site. The mean diameter and polydispersity index of the pored MPs were measured by a particle size analyzer to be 37.6 ± 1.3 µm and 1.15, respectively. The drug loading capacity of the co-delivery system was shown to be 50-times higher than previously reported pored MPs. Fluorescence microscopy analysis of sulforhodamine B (into a hollow interior of HNTs)/ fluorescent nanoparticles (into a hollow interior of MPs)-encapsulated MPs confirmed biphasic release behavior due to pH-dependent pore closing/opening in the simulated gastrointestinal (GI) digestive conditions. To verify the protective effect of the co-delivery system, bromelain and lactase were loaded into HNTs and MPs, respectively, and found to exhibit 94.5 ± 3.3% (bromelain) and 70 ± 14.1% (lactase) functional activity in simulated GI tract conditions. The considerable improvement in the stability of the encapsulated enzymes against gastric conditions are attributed to the efficient pore sealing of the co-delivery system after the encapsulation of enzymes and maintenance of these closed pores in the gastric environment. Furthermore, the mucolytic enzyme (i.e. bromelain)-encapsulated co-delivery system was found to enhance mucopenetration of the encapsulated drug from histological analysis using ex vivo porcine intestine tissue. Therefore, the new microencapsulation design proposed in this study provides a promising solution to the major issues hampering the wide-spread application of MPs in the development of oral drug formulations for biopharmaceuticals and vaccines.