A quality by design approach to optimise disulfide-linked hyaluronic acid hydrogels.

In this study, the disulfide-linked hyaluronic acid (HA) hydrogels were optimised for potential application as a scaffold in tissue engineering through the Quality by Design (QbD) approach. For this purpose, HA was first modified by incorporating the cysteine moiety into the HA backbone, which promoted the formation of disulfide cross-linked HA hydrogel at physiological pH. Utilising a Design of Experiments (DoE) methodology, the critical factors to achieve stable biomaterials, i.e. the degree of HA substitution, HA molecular weight, and coupling agent ratio, were explored. To establish a design space, the DoE was performed with 65 kDa, 138 kDa and 200 kDa HA and variable concentrations of coupling agent to optimise conditions to obtain HA hydrogel with improved rheological properties. Thus, HA hydrogel with a 12 % degree of modification, storage modulus of ≈2321 Pa and loss modulus of ≈15 Pa, was achieved with the optimum ratio of coupling agent. Furthermore, biocompatibility assessments in C28/I2 chondrocyte cells demonstrated the non-toxic nature of the hydrogel, underscoring its potential for tissue regeneration. Our findings highlight the efficacy of the QbD approach in designing HA hydrogels with tailored properties for biomedical applications.

Targeting of M2 macrophages with IL-13-functionalized liposomal prednisolone inhibits melanoma angiogenesis in vivo.

The intricate cooperation between cancer cells and nontumor stromal cells within melanoma microenvironment (MME) enables tumor progression and metastasis. We previously demonstrated that the interplay between tumor-associated macrophages (TAMs) and melanoma cells can be disrupted by using long-circulating liposomes (LCLs) encapsulating prednisolone phosphate (PLP) (LCL-PLP) that inhibited tumor angiogenesis coordinated by TAMs. In this study, our goal was to improve LCL specificity for protumor macrophages (M2-like (i.e., TAMs) macrophages) and to induce a more precise accumulation at tumor site by loading PLP into IL-13-conjugated liposomes (IL-13-LCL-PLP), since IL-13 receptor is overexpressed in this type of macrophages. The IL-13-LCL-PLP liposomal formulation was obtained by covalent attachment of thiolated IL-13 to maleimide-functionalized LCL-PLP. C57BL/6 mice bearing B16.F10 s.c melanoma tumors were used to investigate the antitumor action of LCL-PLP and IL-13-LCL-PLP. Our results showed that IL-13-LCL-PLP formulation remained stable in biological fluids after 24h and it was preferentially taken up by M2 polarized macrophages. IL-13-LCL-PLP induced strong tumor growth inhibition compared to nonfunctionalized LCL-PLP at the same dose, by altering TAMs-mediated angiogenesis and oxidative stress, limiting resistance to apoptosis and invasive features in MME. These findings suggest IL-13-LCL-PLP might become a promising delivery platform for chemotherapeutic agents in melanoma.

Polyvinyl Alcohol, a Versatile Excipient for Pharmaceutical 3D Printing.

Three-dimensional (3D) printing in the pharmaceutical field allows rapid manufacturing of a diverse range of pharmaceutical dosage forms, including personalized items. The application of this technology in dosage form manufacturing requires the judicious selection of excipients because the selected materials must be appropriate to the working principle of each technique. Most techniques rely on the use of polymers as the main material. Among the pharmaceutically approved polymers, polyvinyl alcohol (PVA) is one of the most used, especially for fused deposition modeling (FDM) technology. This review summarizes the physical and chemical properties of pharmaceutical-grade PVA and its applications in the manufacturing of dosage forms, with a particular focus on those fabricated through FDM. The work provides evidence on the diversity of dosage forms created using this polymer, highlighting how formulation and processing difficulties may be overcome to get the dosage forms with a suitable design and release profile.

Process development of inhalation powders containing simvastatin loaded liposomes using spray drying technology.

The development of an inhalation powder (IP) for cancer therapy is desired to improve the therapeutic response and patient compliance. The latest studies highlighted that statins, a class of drugs used in hypercholesterolemia, can have anticancer and antiinflammatory properties. Therefore, the aim of the study was to develop an IP containing liposomes loaded with simvastatin using spray drying technology, as well as to investigate the influence of formulation factors on the quality attributes of the IP by means of experimental design. Results highlighted that the composition of liposomes, namely type of phospholipid and cholesterol concentration, highly influences the quality attributes of IP, and the use of optimal concentrations of excipients, i.e. D-mannitol and L-leucine, is essential to preserve the characteristics of liposomes throughout the spray drying process. The in vitro characterization of the optimal IP formulation revealed that the total percentage of released drug is higher from the IP formulation compared to the powder of active substance (53.38 vs. 42.76%) over a period of six hours, and 39.67% of dry particles have a size less than 5 µm, making them suitable for inhalation. As a conclusion, spray drying technology can be effectively used in the development and preparation of IP containing liposomes.

Development of a Bilayer Tablet by Fused Deposition Modeling as a Sustained-Release Drug Delivery System.

Three-dimensional printing by fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) is a point of convergence of research efforts directed toward the development of personalized dosage forms. In addition to the customization in terms of shapes, sizes, or delivered drug doses, the modulation of drug release profiles is crucial to ensure the superior efficacy and safety of modern 3D-printed medications compared to those of conventional ones. Our work aims to solidify the groundwork for the preparation of 3D-printed tablets that ensure the sustained release of diclofenac sodium. Specifically, we achieved the fast release of a diclofenac sodium dose to allow for the prompt onset of its pharmacological effect, further sustaining by the slow release of another dose to maintain the effect over a prolonged timeframe. In this regard, proper formulation and design strategies (a honeycomb structure for the immediate-release layer and a completely filled structure for the sustained-release layer) were applied. Secondarily, the potential of polyvinyl alcohol to function as a multifaceted polymeric matrix for both the immediate and slow-release layers was explored, with the objective of promoting the real-life applicability of the technique by downsizing the number of materials required to obtain versatile pharmaceutical products. The present study is a step forward in the translation of HME-FDM-3DP into a pharmaceutical manufacturing methodology.

Development of Diclofenac Sodium 3D Printed Cylindrical and Tubular-Shaped Tablets through Hot Melt Extrusion and Fused Deposition Modelling Techniques.

The present study aimed to develop 3D printed dosage forms, using custom-made filaments loaded with diclofenac sodium (DS). The printed tablets were developed by implementing a quality by design (QbD) approach. Filaments with adequate FDM 3D printing characteristics were produced via hot melt extrusion (HME). Their formulation included DS as active substance, polyvinyl alcohol (PVA) as a polymer, different types of plasticisers (mannitol, erythritol, isomalt, maltodextrin and PEG) and superdisintegrants (crospovidone and croscarmellose sodium). The physicochemical and mechanical properties of the extruded filaments were investigated through differential scanning calorimetry (DSC), X-ray diffraction (XRD) and tensile measurements. In addition, cylindrical-shaped and tubular-shaped 3D dosage forms were printed, and their dissolution behaviour was assessed via various drug release kinetic models. DSC and XRD results demonstrated the amorphous dispersion of DS into the polymeric filaments. Moreover, the 3D printed tablets, regardless of their composition, exhibited a DS release of nearly 90% after 45 min at pH 6.8, while their release behaviour was effectively described by the Korsmeyer-Peppas model. Notably, the novel tube design, which was anticipated to increase the drug release rate, proved the opposite based on the in vitro dissolution study results. Additionally, the use of crospovidone increased DS release rate, whereas croscarmellose sodium decreased it.

The Use of the QbD Approach to Optimize the Co-Loading of Simvastatin and Doxorubicin in Liposomes for a Synergistic Anticancer Effect.

The present study aimed to optimize a liposomal formulation co-encapsulating simvastatin (SIM) and doxorubicin (DOX) that has future perspectives in anticancer therapy. The optimization process was performed by implementing the Quality by Design concept and by considering the results of a previous screening study. Failure Mode and Effects Analysis was used for the identification of the potential critical factors, i.e., phospholipid, SIM and DOX concentration, which were assessed in an optimization experimental design with the purpose of designing an optimal formulation. The optimal formulation, meeting the established quality profile, was additionally characterized in terms of the release profile and antiproliferative effects. During dissolution studies, a novel chronoamperometric method was used for the simultaneous quantification of SIM and DOX. The obtained data confirmed the similarity of this method with a validated HPLC method. The anticancer potential of the optimal formulation was tested against two human cancerous cell lines, namely T47D-KBluc human mammary ductal carcinoma cell line and A549 human pulmonary cancer cell line. The results highlighted that the antiproliferative effect of the optimal formulation is concentration dependent and favors a synergistic effect of the two drugs.

Curcumin-Loaded Microspheres Are Effective in Preventing Oxidative Stress and Intestinal Inflammatory Abnormalities in Experimental Ulcerative Colitis in Rats.

Curcumin's role in the treatment of ulcerative colitis (UC) has been proven by numerous studies, but its preventive administration, with the aim of reducing the remission episodes that are characteristic of this disease, must be further investigated. This study investigates the effects of a novel curcumin-loaded polymeric microparticulate oral-drug-delivery system for colon targeting (Col-CUR-MPs) in an experimental model of UC. Male Wistar rats (n = 40) were divided into five groups (n = 8), which were treated daily by oral gavage for seven days with a 2% aqueous solution of carboxymethylcellulose sodium salt (CMCNa) (healthy and disease control), free curcumin powder (reference), Col-CUR-MPs (test) and prednisolone (reference) prior to UC induction by the intrarectal administration of acetic acid (AA), followed by animal sacrification and blood and colonic samples' collection on the eighth day. Col-CUR-MPs exhibited an important preventive effect in the severity degree of oxidative stress that resulted following AA intrarectal administration, which was proved by the highest catalase (CAT) and total antioxidant capacity (TAC) levels and the lowest nitrites/nitrates (NOx), total oxidative status (TOS) and oxidative stress index (OSI) levels. Biochemical parameter analysis was supported by histopathological assessment, confirming the significant anti-inflammatory and antioxidant effects of this novel colon-specific delivery system in AA-induced rat models of UC. Thus, this study offers encouraging perspectives regarding the preventive administration of curcumin in the form of a drug delivery system for colon targeting.

Orally Dispersible Dosage Forms for Paediatric Use: Current Knowledge and Development of Nanostructure-Based Formulations.

The paediatric population has always suffered from a lack of medicines tailored to their needs, especially in terms of accurate dosage, stability and acceptability. Orodispersible dosage forms have gone through a resurrection as an alternative to liquid formulations or fractioned solid formulations, although they are still subject to several inconveniences, among which the unpleasant taste and the low oral bioavailability of the API are the most significant hurdles in the way of achieving an optimal drug product. Nanostructures can address these inconveniences through their size and variety, owing to the plethora of materials that can be used in their manufacturing. Through the formation and functionalisation of nanostructures, followed by their inclusion in orodispersible dosage forms, safe, stable and acceptable medicines intended for paediatric use can be developed.

An Overview of the Supramolecular Systems for Gene and Drug Delivery in Tissue Regeneration.

Tissue regeneration is a prominent area of research, developing biomaterials aimed to be tunable, mechanistic scaffolds that mimic the physiological environment of the tissue. These biomaterials are projected to effectively possess similar chemical and biological properties, while at the same time are required to be safely and quickly degradable in the body once the desired restoration is achieved. Supramolecular systems composed of reversible, non-covalently connected, self-assembly units that respond to biological stimuli and signal cells have efficiently been developed as preferred biomaterials. Their biocompatibility and the ability to engineer the functionality have led to promising results in regenerative therapy. This review was intended to illuminate those who wish to envisage the niche translational research in regenerative therapy by summarizing the various explored types, chemistry, mechanisms, stimuli receptivity, and other advancements of supramolecular systems.

A Quality by Design Approach in Pharmaceutical Development of Non-Viral Vectors with a Focus on miRNA.

Cancer is the leading cause of death worldwide. Tumors consist of heterogeneous cell populations that have different biological properties. While conventional cancer therapy such as chemotherapy, radiotherapy, and surgery does not target cancer cells specifically, gene therapy is attracting increasing attention as an alternative capable of overcoming these limitations. With the advent of gene therapy, there is increasing interest in developing non-viral vectors for genetic material delivery in cancer therapy. Nanosystems, both organic and inorganic, are the most common non-viral vectors used in gene therapy. The most used organic vectors are polymeric and lipid-based delivery systems. These nanostructures are designed to bind and protect the genetic material, leading to high efficiency, prolonged gene expression, and low toxicity. Quality by Design (QbD) is a step-by-step approach that investigates all the factors that may affect the quality of the final product, leading to efficient pharmaceutical development. This paper aims to provide a new perspective regarding the use of the QbD approach for improving the quality of non-viral vectors for genetic material delivery and their application in cancer therapy.

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis.

Primary melanoma aggressiveness is determined by rapid selection and growth of cellular clones resistant to conventional treatments, resulting in metastasis and recurrence. In addition, a reprogrammed tumor-immune microenvironment supports melanoma progression and response to therapy. There is an urgent need to develop selective and specific drug delivery strategies for modulating the interaction between cancer cells and immune cells within the tumor microenvironment. This study proposes a novel combination therapy consisting of sequential administration of simvastatin incorporated in IL-13-functionalized long-circulating liposomes (IL-13-LCL-SIM) and doxorubicin encapsulated into PEG-coated extracellular vesicles (PEG-EV-DOX) to selectively target both tumor-associated macrophages and melanoma cells. To this end, IL-13 was conjugated to LCL-SIM which was obtained via the lipid film hydration method. EVs enriched from melanoma cells were passively loaded with doxorubicin. The cellular uptake of rhodamine-tagged nano-particles and the antiproliferative potential of the treatments by using the ELISA BrdU-colorimetric immunoassay were investigated in vitro. Subsequently, the therapeutic agents were administered i.v in B16.F10 melanoma-bearing mice, and tumor size was monitored during treatment. The molecular mechanisms of antitumor activity were investigated using angiogenic and inflammatory protein arrays and western blot analysis of invasion (HIF-1) and apoptosis markers (Bcl-xL and Bax). Quantification of oxidative stress marker malondialdehyde (MDA) was determined by HPLC. Immunohistochemical staining of angiogenic markers CD31 and VEGF and of pan-macrophage marker F4/80 was performed to validate our findings. The in vitro data showed that IL-13-functionalized LCL were preferentially taken up by tumor-associated macrophages and indicated that sequential administration of IL-13-LCL-SIM and PEG-EV-DOX had the strongest antiproliferative effect on tumor cells co-cultured with tumor-associated macrophages (TAMs). Accordingly, strong inhibition of tumor growth in the group treated with the sequential combination therapy was reported in vivo. Our data suggested that the antitumor action of the combined treatment was exerted through strong inhibition of several pro-angiogenic factors (VEGF, bFGF, and CD31) and oxidative stress-induced upregulation of pro-apoptotic protein Bax. This novel drug delivery strategy based on combined active targeting of both cancer cells and immune cells was able to induce a potent antitumor effect by disruption of the reciprocal interactions between TAMs and melanoma cells.

Protective Effect of Liposomal Epigallocatechin-Gallate in Experimental Gentamicin-Induced Hepatotoxicity.

Our study aimed to assess the effect of liposomal epigallocatechin-gallate (LEGCG) compared with epigallocatechin-gallate (EGCG) solution on hepatic toxicity induced by gentamicin (G) administration in rats. Five groups were evaluated, a control group (no G administration) and four groups that received G (1 mL, i.p, 80 mg/kg b.w. (body weight/day), for 7 days) to which we associated daily administration 30 min before G of EGCG (G-EGCG, 2.5 mg/0.1 kg b.w.), LEGCG (G-LEGCG, 2.5 mg/0.1 kg b.w.) or silymarin (100 mg/kg b.w./day). The nitro-oxidative stress (NOx), catalase (CAT), TNF-α, transaminases, creatinine, urea, metalloproteinase (MMP) 2 and 9, and liver histopathological changes were evaluated. LEGCG exhibited better efficacy than EGCG, improving the oxidant/antioxidant balance (p = 0.0125 for NOx and 0.0032 for CAT), TNF-α (p < 0.0001), MMP-2 (p < 0.0001), aminotransferases (p = 0.0001 for AST and 0.0136 for ALT), creatinine (p < 0.0001), urea (p = 0.0006) and histopathologic liver changes induced by gentamicin. Our study demonstrated the beneficial effect of EGCG with superior results of the liposomal formulation for hepatoprotection in experimental hepatic toxicity induced by gentamicin.

In-Depth Understanding of Granule Compression Behavior under Variable Raw Material and Processing Conditions.

Tablet manufacturing involves the processing of raw materials through several unit operations. Thus, the mitigation of input-induced variability should also consider the downstream processability of intermediary products. The objective of the present work was to study the effect of variable raw materials and processing conditions on the compression properties of granules containing two active pharmaceutical ingredients (APIs) and microcrystalline cellulose. Differences in compressibility and tabletability of granules were highlighted in function of the initial particle size of the first API, granule polydispersity and fragmentation. Moreover, interactions were underlined with the atomizing pressure. Changing the supplier of the second API was efficiently controlled by adapting the binder addition rate and atomizing pressure during granulation, considering the starting crystal size. By fitting mathematical models on the available compression data, the influence of diluent source on granule compactibility and tabletability was identified. These differences resumed to the ease of compaction, tableting capacity and pressure sensitivity index due to variable water binding capacity of microcrystalline cellulose. Building the design space enabled the identification of suitable API types and the appropriate processing conditions (spray rate, atomizing pressure, compression force) required to ensure the desired tableting performance.

Trojan horse treatment based on PEG-coated extracellular vesicles to deliver doxorubicin to melanoma in vitro and in vivo.

Tailoring extracellular vesicles (EVs) as targeted drug delivery systems to enhance the therapeutic efficacy showed superior advantage over liposomal therapies. Herein, we developed a novel nanotool for targeting B16.F10 murine melanoma, based on EVs stabilized with Polyethylene glycol (PEG) and loaded with doxorubicin (DOX). Small EVs were efficiently enriched from melanoma cells cultured under metabolic stress by ultrafiltration coupled with size exclusion chromatography (UF-SEC) and characterized by size, morphology, and proteome. To reduce their clearance in vivo, EVs were PEGylated and passively loaded with DOX (PEG-EV-DOX). Our data suggested that the low PEG coverage of EVs might still favor EV surface protein interactions with target proteins from intratumor cells, ensuring their use as "Trojan horses" to deliver DOX to the tumor tissue. Moreover, our results showed a superior antitumor activity of PEG-EV-DOX in B16.F10 murine melanoma models in vivo compared to that exerted by clinically applied liposomal DOX in the same tumor model. The PEG-EV-DOX administration in vivo reduced NF-κB activation and increased BAX expression, suggesting better prognosis of EV-based therapy than liposomal DOX treatment. Collectively, our results highlight the promising potential of EVs as optimal tools for systemic delivery of DOX to solid tumors.

QbD guided development of immediate release FDM-3D printed tablets with customizable API doses.

The objective of this work was to develop a fused deposition modeling (FDM) 3D printed immediate release (IR) tablet with flexibility in adjusting the dose of the active pharmaceutical ingredient (API) by scaling the size of the dosage form and appropriate drug release profile steadiness to the variation of dimensions or thickness of the deposited layers throughout the printing process. Polyvinyl alcohol-based filaments with elevated API content (50% w/w) were prepared by hot melt extrusion (HME), through systematic screening of polymeric formulations with different drug loadings, and their printability was evaluated by means of mechanical characterization. For the tablet fabrication step by 3D printing (3DP), the Quality by Design (QbD) approach was implemented by employing risk management strategies and Design of Experiments (DoE). The effects of the tablet design, tablet size and the layer height settings on the drug release and the API content were investigated. Between the two proposed original tablet architectures, the honeycomb configuration was found to be a suitable candidate for the preparation of IR dosage forms with readily customizable API doses. Also, a predictive model was obtained, which assists the optimization of variables involved in the printing phase and thereby facilitates the tailoring process.

Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression.

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.

A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy.

An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.

Polyvinyl Alcohol-Based 3D Printed Tablets: Novel Insight into the Influence of Polymer Particle Size on Filament Preparation and Drug Release Performance.

Three-dimensional printing (3DP) by fused deposition modeling (FDM) has gained momentum as a promising pharmaceutical manufacturing method due to encouraging forward-looking perspectives in personalized medicine preparation. The current challenges the technology has for applicability in the fabrication of solid dosage forms include the limited range of suitable pharmaceutical grade thermoplastic materials. Hence, it is important to investigate the implications of variable properties of the polymeric carrier on the preparation steps and the final output, as versatile products could be obtained by using the same material. In this study, we highlighted the influence of polyvinyl alcohol (PVA) particle size on the residence time of the mixtures in the extruder during the drug-loaded filament preparation step and the consequent impact on drug release from the 3D printed dosage form. We enhanced filament printability by exploiting the plasticizing potential of the active pharmaceutical ingredient (API) and we explored a channeled tablet model as a design strategy for dissolution facilitating purposes. Our findings disclosed a new perspective regarding material considerations for the preparation of PVA-based solid dosage forms by coupling hot melt extrusion (HME) and FDM-3DP.

Protective Effects of Liposomal Curcumin on Oxidative Stress/Antioxidant Imbalance, Metalloproteinases 2 and -9, Histological Changes and Renal Function in Experimental Nephrotoxicity Induced by Gentamicin.

BACKGROUND: Our study aimed to assess the efficiency of Curcumin nanoformulation (LCC) on experimental nephrotoxicity induced by Gentamicin in rats. METHODS: Six groups of seven rats were used: C-(control group) received saline solution i.p. (i.p. = intraperitoneal), G-gentamicin (G, 80 mg/kg body weight (b.w.)), GCC1 and GCC2-with G and CC solution (single dose of 10 mg/kg b.w.-CC1, or 20 mg/kg b.w.-CC2), GLCC1 (10 mg/kg b.w.) and GLCC2 (20 mg/kg b.w.) with G and LCC administration. Oxidative stress parameters (NOx = nitric oxide, MDA = malondialdehyde, TOS = total oxidative stress), antioxidant parameters (CAT = catalase, TAC = total antioxidant capacity), matrix metalloproteinases (MMP-2 and MMP-9), and renal function parameters (creatinine, blood urea nitrogen, and urea) were measured. Kidneys histopathologic examination was made for each group. RESULTS: Pretreatment with CC and LCC in both doses had significantly alleviating effects on assessed parameters (NOx, MDA, TOS, CAT, TAC, MMP-2, and -9) as compared with the untreated group (p < 0.006). Histopathological aspect and renal function were significantly improved in CC and LCC groups. Liposomal formulation (LCC) showed higher efficiency on all examined parameters compared to CC (p < 0.006). CONCLUSIONS: Our results demonstrated improving renal function and kidney cytoarchitecture, oxidative stress/antioxidant/balance, and MMPs plasma concentrations with better dose-related efficacity of LCC than CC.