Journal

International Journal of Pharmaceutics

Papers (33)

Follicle-stimulating hormone peptide-conjugated liposomes in the treatment of epithelial ovarian cancer through the induction of M2-to-M1 macrophage repolarization

The silent killer epithelial ovarian cancer (EOC) is a lethal malignancy with high mortality rate and often diagnosed at an advanced stage. Traditional chemotherapy for EOC remains unsatisfactory as the tumor microenvironment (TME) is complicated and contains multiple factors such as tumor associated macrophages (TAMs). Therefore, a drug delivery system which codelivery chemotherapy drug and immune modulator for EOC treatment is urgently needed. Follicle-stimulating hormone peptide-conjugated paclitaxel and ginsenoside Rh2 codelivery liposomes (FSH@PTX-Rh2-Lips) were prepared in this study. FSH was decorated on the liposomal surface to enhance cellar uptake, PTX was used to kill cancer cells, and Rh2 was added to induce macrophages repolarization as well as a member material. The targeting, anti-tumor effect and impact on macrophage repolarization of FSH@PTX-Rh2-Lips were evaluated in vitro and in vivo. With the ideal physicochemical properties, FSH@PTX-Rh2-Lips displayed increased cellular uptake, strong cytotoxicity to ID8 cells, inhibitory effect of tumor cell metastasis, and ability to induce macrophage repolarization from M2 to M1 in vitro. The tumor-bearing mice model suggested FSH@PTX-Rh2-Lips showed significant effect on antitumor and tumor recurrence, and the mechanism of FSH@PTX-Rh2-Lips in treatment of EOC was related to inhibiting tumor growth and inducing macrophage repolarization. FSH@PTX-Rh2-Lips with function of affecting TAMs repolarization and altering the TME were successfully prepared and might offer an effective therapeutic strategy against EOC.

Multiple hour antifibrotic drug release enabled by a thermosensitive quadpolymer

Injectable drug delivery for uterine fibroid therapy is an ambitious, possibly fertility-preserving concept, that could meet the challenges associated with the structure of these tumors and their location in the uterus. This study was conducted to advance a thermosensitive injectable quadpolymer for effective sustained release of anti-fibrotic drug formulations and to evaluate the feasibility of its use for delivery of the anti-fibrotic drug pirfenidone as a therapy to reduce fibroid cell proliferation. A series of quadpolymers were prepared by free radical polymerization of N-isopropylacrylamide (NIPAM) with different amounts of polylactic acid functionalized hydroxyethyl methacrylate (HEMA-PLA), acrylic acid (AAc), and methacrylate functionalized hyperbranched polyglycerol (HPG-MA) to optimize the sol-gel phase transition temperature and mechanical stiffness. Poly(NIPAM-co-HEMA-PLA-co-AAc-co-HPG-MA) with feed ratio (83-7-1-9), at 17% w/v, readily formed an aqueous solution that could be manipulated by syringe at room temperature. The quadpolymer also rapidly formed a stable gel at physiological body temperature, and partially biodegraded over time as confirmed by several spectroscopic characterization techniques. To evaluate the potential range of utility, quadpolymer 83-7-1-9 was loaded in-vitro with caffeine (a prototype hydrophilic drug) or the hydrophobic drug pirfenidone. Pirfenidone-loaded quadpolymer 83-7-1-9 formulations released 50% of drug loaded in double the time as compared to other reported liposome and nanoparticle injectable pirfenidone formulations. Furthermore, treatment of cultured fibroid cells with pirfenidone-loaded quadpolymer 83-7-1-9 formulations confirmed that activity of pirfenidone was preserved and proliferation of fibroid cells was inhibited. These results support that quadpolymer 83-7-1-9 is a promising candidate to be further developed for localized delivery of drugs for uterine fibroid therapy.

Formation of amygdalin/β-cyclodextrin derivatives inclusion complexes for anticancer activity assessment in human cervical carcinoma HeLa cell line

Nanoencapsulation has gained considerable attention because of its unique features and advantages in anticancer drug delivery. Amygdalin (AMY) is an anticancer compound, showing limitations in its applications by low stability. Herein, the inclusion complexes (ICs) of AMY with β-cyclodextrin (βCD), and its derivatives such as 2-hydroxypropyl-βCD (HPβCD) and methyl-βCD (MβCD) were fabricated. The fabricated AMY/CD-ICs were thoroughly evaluated using Fourier-transform infrared spectroscopy, powder X-ray diffraction, thermogravimetric/differential thermal analysis, proton nuclear magnetic resonance, ultraviolet-visible diffuse reflectance spectroscopy, and photoluminescence techniques. Double reciprocal profile study of the absorption and fluorescence spectra revealed that the AMY formed the ICs with βCD derivatives at a guest/host stoichiometric ratio of 1/1. The thermal stability of AMY was enhanced as the IC formation aid observed by the shift of thermal degradation temperature of AMY from the range of ∼ 220-250 °C to > 295 °C. Theoretical analyses of the energetic, electronic, and global reactivity parameters of the AMY/CD-ICs were evaluated using the PM3 method. Further assessment of the dissolution diagrams of AMY/CD-ICs revealed a burst release profile. In addition, cell toxicity was evaluated using the MTT assay, and the results showed that AMY/CD-ICs had significantly more efficacious in inhibiting HeLa cancer cells than AMY. These results proved that the IC formations with CDs significantly enhanced the anticancer activity of AMY.

Hypoxia-sensitive micellar nanoparticles for co-delivery of siRNA and chemotherapeutics to overcome multi-drug resistance in tumor cells

Recently, it has been discovered that the PEG layer on nanoparticle surface can create steric hindrance, preventing efficient cellular uptake of PEGylated nanoparticles. Thus, it would be ideal to have a nanoparticle system that sheds the PEG layer upon reaching the tumor microenvironment. Hypoxia, which is a hallmark of cancerous tumors, can be used as a trigger to shed the PEG layer from the nanoparticle surface. In this study, a hypoxia-sensitive PEG-azobenzene-PEI-DOPE (PAPD) construct, with an azobenzene group as a hypoxia-sensitive moiety, was prepared. The feasibility of co-delivering Doxorubicin (Dox) and anti-P-gp siRNA (siPgp) using the PAPD nanoparticles was evaluated in monolayers of the Adriamycin-resistant human ovarian cancer cell line, A2780 ADR, and in 3D spheroids of the multidrug-resistant human breast cancer cell line, MCF7 ADR. Under hypoxic conditions, the PAPD nanoparticles showed up to a 60% increase in cellular uptake by monolayers and a significantly greater tumor penetration in a spheroid model. siPgp, when delivered using PAPD nanoparticles, showed up to a 60% P-gp downregulation under hypoxic conditions. The combination of siPgp and Dox delivered using PAPD nanoparticles led to an 80% cytotoxicity in cell monolayers and 20% cytotoxicity in spheroids under hypoxic conditions. In this research, a novel hypoxia-sensitive nanoparticle system was developed that demonstrated improved delivery of an encapsulated cargo and augmented cytotoxicity on multidrug-resistant cancer cells under hypoxic conditions.

Enhanced docetaxel delivery using sterically stabilized RIPL peptide-conjugated nanostructured lipid carriers: In vitro and in vivo antitumor efficacy against SKOV3 ovarian cancer cells

Docetaxel (DTX) has poor solubility, low specificity, and severe side effects. For efficient targeting of DTX to hepsin-overexpressing SKOV3 ovarian cancer cells, PEGylated and RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (PEG-RIPL-NLCs) were examined for in vitro and in vivo antitumor efficacy. DTX-loaded plain NLCs (DTX-pNLCs), RIPL-NLCs (DTX-RIPL-NLCs), and PEG-RIPL-NLCs (DTX-PEG-RIPL-NLCs) were prepared using a solvent emulsification-evaporation technique. DTX was successfully loaded with high encapsulation efficiency (>93%), and all NLCs showed homogeneous dispersion with zeta potentials varying from -17 to 15 mV. Drug release was biphasic: initial rapid release, then gradual release. In vitro cytotoxicity was time- and dose-dependent: DTX-RIPL-NLCs and DTX-PEG-RIPL-NLCs exhibited greater cytotoxicity, enhanced cell apoptosis owing to the cell cycle arrest in the G2/M phase, and increased activation of the mitochondria-related intrinsic apoptosis pathway compared to DTX-pNLCs. Pharmacokinetic experiments in male Sprague-Dawley rats revealed that DTX-PEG-RIPL-NLCs increased the mean residence time of DTX but reduced total body clearance and volume of distribution. In a SKOV3-bearing xenograft Balb/c athymic mouse model, DTX-PEG-RIPL-NLCs suppressed tumors, evidenced by tumor volume change and histopathological examination. Thus, we conclude that PEG-RIPL-NLCs have an advantage of high payload of poorly water-soluble drugs and are a good candidate for drug targeting to SKOV3-derived ovarian cancer.

Epirubicin/folic acid and meropenem loaded on graphene oxide-gelatin can be used as a novel candidate for anti-cancer and antibacterial drug development

Resistance to meropenem and epirubicin poses a significant global threat, particularly in developing nations with constrained health resources. To overcome this problem, nanotechnology provides several promising solutions, including drug delivery systems that can improve the effectiveness of drugs. The objectives of this work is to characterize the anticancer mechanism of Graphene Oxide (GO) coated with Gelatin (Gel) and conjugated with the anticancer drug Epirubicin (EPi), along with functionalization with Folic Acid in SK-OV3 cancer cell lines for the first time. Furthermore, meropenem was loaded onto Graphene Oxide-Gelatin (GO-Gel) to improve its efficacy. The nanocomposites were characterized using FT-IR, XRD, FESEM and EDX. The viability of the ovarian cancer cell lines (SKOV3) and normal ovarian cell lines (HUVEC) after treatment with GO-Gel, Graphene Oxide-Gelatin-Folic acid (GO-Gel-FA), free Epi and Graphene Oxide-Gelatin-Folic acid/ Epirubicin (GO-Gel-FA/Epi) nanocomposite, was studied by the MTT assay. Expression of the TNFα, Bax, Bcl-2, and NF-κB in the GO-Gel-FA/Epi nanocomposite treated cells, were investigated by qRT-PCR. Disc diffusion assay was utilized to assess the antimicrobial activity of free mer and GO-Gel-Mer nanocomposite against two gram-positive bacteria and two gram-negative bacteria. Results demonstrated that The GO-Gel-FA/Epi nanocomposite showed greater cytotoxic effects on SKOV3cells than normal HUVEC cells. The expression of the Bax was upregulated, while the expression of the Bcl-2, TNFα and NF-κB was reduced in GO-Gel-FA/Epi nanocomposite-treated cells. The Graphene Oxide-Gelatin-Meropenem (GO-Gel-Mer) nanocomposite showed a controlled release within 45 h. GO-Gel-Mer nanocomposite showed much more activity against bacteria in comparison to free Mer. GO-Gel-FA/Epi nanocomposite possesses strong anti-proliferative properties against SK-OV3 cancer cells and indicated promising inhibitory candidate for anticancer therapy. The novel synthesized GO-Gel-Mer nanocomposite can be used as an effective antimicrobial nanomaterial against a range of microbial pathogens, including gram-negative and gram-positive bacteria.

Co-delivery of Paclitaxel/Atovaquone/Quercetin to regulate energy metabolism to reverse multidrug resistance in ovarian cancer by PLGA-PEG nanoparticles

Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.

Targeting ovarian cancer: The promise of liposome-based therapies

A major cause of mortality among gynecological cancers, ovarian cancer is frequently unresponsive to standard therapies because to systemic toxicity and medication resistance. The contribution of liposomal drug delivery systems, specifically pegylated liposomal doxorubicin (PLD), to the advancement of ovarian cancer treatment is examined in this review. Liposomes, spherical lipid vesicles consisting of bilayer phospholipids, enable better drug delivery by preserving encapsulated pharmaceuticals and enabling tailored administration to tumor areas. In comparison to traditional doxorubicin, PLD has a better pharmacokinetic profile and less cardiotoxicity, according to the analysis, which examines several trials showing its effectiveness in treating both platinum-sensitive and platinum-resistant ovarian cancer. Furthermore, studies on liposomal versions of other medications, such as paclitaxel and cisplatin, demonstrate encouraging effects in terms of overcoming drug resistance and enhancing therapeutic outcomes. Recent advancements in tailored liposomal delivery systems that include components such tumor-specific peptides and folate receptors show improved tumor selectivity and fewer adverse effects. The study also looks at new combination treatments that use liposomal formulations with immunotherapeutic and new targeted medicines. Although liposomal drug delivery methods have great potential for treating ovarian cancer, further study is required to maximize their effectiveness, reduce side effects, and get beyond resistance mechanisms. These developments in liposomal technology are a major step toward turning ovarian cancer from a deadly illness into a chronic condition that can be managed, possibly increasing patient survival and quality of life.

pH-sensitive niosomes for ATRA delivery: A promising approach to inhibit Pin1 in high-grade serous ovarian cancer

The peptidyl-prolyl cis/trans isomerase Pin1 positively regulates numerous cancer-driving pathways, and it is overexpressed in several malignancies, including high-grade serous ovarian cancer (HGSOC). The findings that all-trans retinoic acid (ATRA) induces Pin1 degradation strongly support that ATRA treatment might be a promising approach for HGSOC targeted therapy. Nevertheless, repurposing ATRA into the clinics for the treatment of solid tumors remains an unmet need mainly due to the insurgence of resistance and its ineffective delivery. In the present study, niosomes have been employed for improving ATRA delivery in HGSOC cell lines. Characterization of niosomes including hydrodynamic diameter, ζ-potential, morphology, entrapment efficiency and stability over time and in culture media was performed. Furthermore, pH-sensitiveness and ATRA release profile were investigated to demonstrate the capability of these vesicles to release ATRA in a stimuli-responsive manner. Obtained results documented a nanometric and monodispersed samples with negative ζ-potential. ATRA was efficiently entrapped, and a substantial release was observed in the presence of acidic pH (pH 5.5). Finally, unloaded niosomes showed good biocompatibility while ATRA-loaded niosomes significantly increased ATRA Pin1 inhibitory activity, which was consistent with cell growth inhibition. Taken together, ATRA-loaded niosomes might represent an appealing therapeutic strategy for HGSOC therapy.

Emerging Trends in cervical cancer Treatment: Transitioning from traditional to innovative delivery strategies

Cervical cancer (CC) remains the second most common cause of cancer-related deaths among women in the United States, following breast cancer. As per American Cancer Society reports, with approximately 4,320 deaths expected annually, it continues to pose a significant threat to global public health. The highest prevalence of CC has been reported in low to middle-income nations in Asia, Africa, and Latin America, where screening and treatment are scarce. Although surgery, radiation therapy, and chemotherapy have long been the cornerstones of CC care, their drawbacks, such as exorbitant expenses, restricted availability, and serious side effects, including neuropathy and infertility, highlight the need for creative alternatives. Current research demonstrates the effectiveness of cutting-edge treatments; for example, pembrolizumab (FDA approval, 2021) immunotherapy has been shown to improve progression-free survival in metastatic CC by 30%. In preclinical models, drug delivery systems based on nanotechnology, such as cisplatin-loaded nanoparticles, have shown a 40% increase in tumor drug concentration with decreased systemic toxicity. By addressing the limitations of existing treatments and concentrating on the pathophysiology of the illness, particularly HPV-driven oncogenesis, this study explores the shift from traditional to advanced CC therapy. It looks at diagnostic innovations such as early detection using MRI and ultrasound, as well as molecular diagnostics with computer-aided methods that have a 25% higher sensitivity in detecting precancerous lesions. The review also discusses therapeutic innovations, ranging from conventional methods like surgery and chemotherapy to newer approaches like photodynamic therapy, which has been shown to reduce tumors by 60% in early-stage CC trials, nanomedicine, targeted therapies (like bevacizumab), localized drug delivery via vaginal gels, nanofibers, intravaginal rings, immunotherapy, and gene therapy. It provides a thorough understanding of the changing treatment environment by analysing ongoing clinical studies and patient patterns.

GLUT1 transporter-facilitated solid lipid nanoparticles loaded with anti-cancer therapeutics for ovarian cancer targeting

The therapeutics available for cancer treatment have the major hurdle of site-specific delivery of anti-cancer drugs to the tumor site and non-target specific side effects. The standard therapy for ovarian cancer still poses numerous pitfalls due to the irrational use of drugs affecting healthy cells. As an appealing approach, nanomedicine could revamp the therapeutic profile of anti-cancer agents. Owing to the low manufacturing cost, increased biocompatibility, and modifiable surface properties, lipid-based nanocarriers, particularly solid lipid nanoparticles (SLN), have remarkable drug delivery properties in cancer treatment. Given the extra-ordinary benefits, we developed anti-neoplastic (paclitaxel) drug-loaded SLN (PTX-SLN) and functionalized with N-acetyl-d-glucosamine (GLcNAc) (GLcNAc-PTX-SLN) to reduce the rate of proliferation, growth, and metastasis of ovarian cancer cells over-expressing GLUT1 transporters. The particles presented considerable size and distribution while demonstrating haemocompatibility. Using GLcNAc modified form of SLNs, confocal microscopy, MTT assay, and flow cytometry study demonstrated higher cellular uptake and significant cytotoxic effect. Also, molecular docking results established excellent binding affinity between GLcNAc and GLUT1, complimenting the feasibility of the therapeutic approach in targeted cancer therapy. Following the compendium of target-specific drug delivery by SLN, our results demonstrated a significant response for ovarian cancer therapy.

Nanotechnology-integrated ovarian cancer metastasis therapy: Insights from the metastatic mechanisms into administration routes and therapy strategies

Ovarian cancer is a kind of malignant tumour which locates in the pelvic cavity without typical clinical symptoms in the early stages. Most patients are diagnosed in the late stage while about 60 % of them have suffered from the cancer cells spreading in the abdominal cavity. The high recurrence rate and mortality seriously damage the reproductive needs and health of women. Although recent advances in therapeutic regimes and other adjuvant therapies improved the overall survival of ovarian cancer, overcoming metastasis has still been a challenge and is necessary for achieving cure of ovarian cancer. To present potential targets and new strategies for curbing the occurrence of ovarian metastasis and the treatment of ovarian cancer after metastasis, the first section of this paper explained the metastatic mechanisms of ovarian cancer comprehensively. Nanomedicine, not limited to drug delivery, offers opportunities for metastatic ovarian cancer therapy. The second section of this paper emphasized the advantages of various administration routes of nanodrugs in metastatic ovarian cancer therapy. Furthermore, the third section of this paper focused on advances in nanotechnology-integrated strategies for targeting metastatic ovarian cancer based on the metastatic mechanisms of ovarian cancer. Finally, the challenges and prospects of nanotherapeutics for ovarian cancer metastasis therapy were evaluated. In general, the greatest emphasis on using nanotechnology-based strategies provides avenues for improving metastatic ovarian cancer outcomes in the future.

Ferrocifen stealth LNCs and conventional chemotherapy: A promising combination against multidrug-resistant ovarian adenocarcinoma

Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug resistance that restricts the success of conventional chemotherapy, carboplatin and paclitaxel. High grade serous ovarian carcinoma can be classified into two subtypes, the chemosensitive High OXPHOS and the Low OXPHOS tumour, less sensitive to chemotherapy. This difference of treatment efficacy could be explained by the redox status of these tumours, High OXPHOS exhibiting a chronic oxidative stress and an accumulation of reactive oxygen species. Ferrocifens, bio-organometallic compounds, are believed to be ROS producers with a good cytotoxicity on ovarian cancer cell lines. The aim of this study was to evaluate the in vivo efficacy of ferrocifen stealth lipid nanocapsules on High and Low OXPHOS ovarian Patient-Derived Xenograft models, alone or in combination to standard chemotherapy. Accordingly, two ferrocifens, P53 and P722, were encapsulated in stealth LNCs. The treatment by stealth P722-LNCs in combination with standard chemotherapy induced, with a concentration eight time lower than in stealth P53-LNCs, similar tumour reduction on a Low OXPHOS model, allowing us to conclude that P722 could be a leading ferrocifen to treat ovarian cancer. This combination of treatments may represent a promising synergistic approach to treat resistant ovarian adenocarcinoma.

Publisher

Elsevier BV

ISSN

0378-5173