PSMA-targeted combination brusatol and docetaxel nanotherapeutics for the treatment of prostate cancer.

Active targeting to cancer involves exploiting specific interactions between receptors on the surface of cancer cells and targeting moieties conjugated to the surface of vectors such that site-specific delivery is achieved. Prostate specific membrane antigen (PSMA) has proved to be an excellent target for active targeting to prostate cancer. We report the synthesis and use of a PSMA-specific ligand (Glu-NH-CO-NH-Lys) for the site-specific delivery of brusatol- and docetaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles to prostate cancer. The PSMA targeting ligand covalently linked to PLGA-PEG3400 was blended with methoxyPEG-PLGA to prepare brusatol- and docetaxel-loaded nanoparticles with different surface densities of the targeting ligand. Flow cytometry was used to evaluate the impact of different surface densities of the PSMA targeting ligand in LNCaP prostate cancer cells at 15 min and 2 h. Cytotoxicity evaluations of the targeted nanoparticles reveal differences based on PSMA expression in PC-3 and LNCaP cells. In addition, levels of reactive oxygen species (ROS) were measured using the fluorescent indicator, H2DCFDA, by flow cytometry. PSMA-targeted nanoparticles loaded with docetaxel and brusatol showed increased ROS generation in LNCaP cells compared to PC-3 at different time points. Furthermore, the targeted nanoparticles were evaluated in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors. Evaluation of the percent relative tumor volume show that brusatol-containing nanoparticles show great promise in inhibiting tumor growth. Our data also suggest that the dual drug-loaded targeted nanoparticle platform improves the efficacy of docetaxel in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors.

Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer.

Challenges to docetaxel use in prostate cancer treatment include several resistance mechanisms as well as toxicity. To overcome these challenges and to improve the therapeutic efficacy in heterogeneous prostate cancer, the use of multiple agents that can destroy different subpopulations of the tumor is required. Brusatol, a multitarget inhibitor, has been shown to exhibit potent anticancer activity and play an important role in drug response and chemoresistance. Thus, the combination of brusatol and docetaxel in a nanoparticle platform for the treatment of prostate cancer is expected to produce synergistic effects. In this study, we reported the development of polymeric nanoparticles for the delivery of brusatol and docetaxel in the treatment of prostate cancer. The one-factor-at-a-time method was used to screen for formulation and process variables that impacted particle size. Subsequently, factors that had modifiable effects on particle size were evaluated using a 24 full factorial statistical experimental design followed by the optimization of drug loading. The optimization of blank nanoparticles gave a formulation with a mean size of 169.1 nm ± 4.8 nm, in agreement with the predicted size of 168.333 nm. Transmission electron microscopy showed smooth spherical nanoparticles. The drug release profile showed that the encapsulated drugs were released over 24 h. Combination index data showed a synergistic interaction between the drugs. Cell cycle analysis and the evaluation of caspase activity showed differences in PC-3 and LNCaP prostate cancer cell responses to the agents. Additionally, immunoblots showed differences in survivin expression in LNCaP cells after treatment with the different agents and formulations for 24 h and 72 h. Therefore, the nanoparticles are potentially suitable for the treatment of advanced prostate cancer.

Development of a Targeted SN-38-Conjugate for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most aggressive and fatal brain tumor, with approximately 10,000 people diagnosed every year in the United States alone. The typical survival period for individuals with glioblastoma ranges from 12 to 18 months, with significant recurrence rates. Common therapeutic modalities for brain tumors are chemotherapy and radiotherapy. The main challenges with chemotherapy for the treatment of glioblastoma are high toxicity, poor selectivity, and limited accumulation of therapeutic anticancer agents in brain tumors as a result of the presence of the blood-brain barrier. To overcome these challenges, researchers have explored strategies involving the combination of targeting peptides possessing a specific affinity for overexpressed cell-surface receptors with conventional chemotherapy agents via the prodrug approach. This approach results in the creation of peptide drug conjugates (PDCs), which facilitate traversal across the blood-brain barrier (BBB), enable preferential accumulation of chemotherapy within the neoplastic microenvironment, and selectively target cancerous cells. This approach increases accumulation in tumors, thereby improving therapeutic efficiency and minimizing toxicity. Leveraging the affinity of the HAIYPRH (T7) peptide for the transferrin receptor (TfR) overexpressed on the blood-brain barrier and glioma cells, a novel T7-SN-38 peptide drug conjugate was developed. The T7-SN-38 peptide drug conjugate demonstrates about a 2-fold reduction in glide score (binding affinity) compared to T7 while maintaining a comparable orientation within the TfR target site using Schrödinger-2022-3 Maestro 13.3 for ligand preparation and Glide SP-Peptide docking. Additionally, SN-38 extends into a solvent-accessible region, enhancing its susceptibility to protease hydrolysis at the cathepsin B (Cat B) cleavable site. The SN-38-ether-peptide drug conjugate displayed high stability in buffer at physiological pH, and cleavage of the conjugate to release free cytotoxic SN-38 was observed in the presence of exogenous cathepsin B. The synthesized peptide drug conjugate exhibited potent cytotoxic activities in cellular models of glioblastoma in vitro. In addition, blocking transferrin receptors using the free T7 peptide resulted in a notable inhibition of cytotoxicity of the conjugate, which was reversed when exogenous cathepsin B was added to cells. This work demonstrates the potential for targeted drug delivery to the brain in the treatment of glioblastoma using the transferrin receptor-targeted T7-SN-38 conjugate.

Colorectal Cancer: Disease Process, Current Treatment Options, and Future Perspectives.

Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university's online library. The keywords were "Colorectal Cancer" AND "disease process" OR "disease mechanisms" OR "Current Treatment" OR "Prospects". Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low-medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin®), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux®) and panitumumab (Verbitix®). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells.

Targeted drug conjugate systems for ovarian cancer chemotherapy.

Ovarian cancer is a highly lethal disease that affects women. Early diagnosis and treatment of women with early-stage disease improve the probability of survival. Unfortunately, the majority of women with ovarian cancer are diagnosed at advanced stages 3 and 4 which makes treatment challenging. While the majority of the patients respond to first-line treatment, i.e. cytoreductive surgery integrated with platinum-based chemotherapy, the rate of disease recurrence is very high and the available treatment options for recurrent disease are not curative. Thus, there is a need for more effective treatment options for ovarian cancer. Targeted drug conjugate systems have emerged as a promising therapeutic strategy for the treatment of ovarian cancer. These systems provide the opportunity to selectively deliver highly potent chemotherapeutic drugs to ovarian cancer, sparing healthy normal cells. Thus, the effectiveness of the drugs is improved and systemic toxicity is greatly reduced. In this review, different targeted drug conjugate systems that have been or are being developed for the treatment of ovarian cancer will be discussed.

Drug Delivery Strategies for the Treatment of Pancreatic Cancer.

Pancreatic cancer is fast becoming a global menace and it is projected to be the second leading cause of cancer-related death by 2030. Pancreatic adenocarcinomas, which develop in the pancreas' exocrine region, are the predominant type of pancreatic cancer, representing about 95% of total pancreatic tumors. The malignancy progresses asymptomatically, making early diagnosis difficult. It is characterized by excessive production of fibrotic stroma known as desmoplasia, which aids tumor growth and metastatic spread by remodeling the extracellular matrix and releasing tumor growth factors. For decades, immense efforts have been harnessed toward developing more effective drug delivery systems for pancreatic cancer treatment leveraging nanotechnology, immunotherapy, drug conjugates, and combinations of these approaches. However, despite the reported preclinical success of these approaches, no substantial progress has been made clinically and the prognosis for pancreatic cancer is worsening. This review provides insights into challenges associated with the delivery of therapeutics for pancreatic cancer treatment and discusses drug delivery strategies to minimize adverse effects associated with current chemotherapy options and to improve the efficiency of drug treatment.

Approaches to Improve Macromolecule and Nanoparticle Accumulation in the Tumor Microenvironment by the Enhanced Permeability and Retention Effect.

Passive targeting is the foremost mechanism by which nanocarriers and drug-bearing macromolecules deliver their payload selectively to solid tumors. An important driver of passive targeting is the enhanced permeability and retention (EPR) effect, which is the cornerstone of most carrier-based tumor-targeted drug delivery efforts. Despite the huge number of publications showcasing successes in preclinical animal models, translation to the clinic has been poor, with only a few nano-based drugs currently being used for the treatment of cancers. Several barriers and factors have been adduced for the low delivery efficiency to solid tumors and poor clinical translation, including the characteristics of the nanocarriers and macromolecules, vascular and physiological barriers, the heterogeneity of tumor blood supply which affects the homogenous distribution of nanocarriers within tumors, and the transport and penetration depth of macromolecules and nanoparticles in the tumor matrix. To address the challenges associated with poor tumor targeting and therapeutic efficacy in humans, the identified barriers that affect the efficiency of the enhanced permeability and retention (EPR) effect for macromolecular therapeutics and nanoparticle delivery systems need to be overcome. In this review, approaches to facilitate improved EPR delivery outcomes and the clinical translation of novel macromolecular therapeutics and nanoparticle drug delivery systems are discussed.

A Six-Semester Integrated Pharmacy Practice Course Based on Entrustable Professional Activities.

Objective. To design and assess the outcomes of a longitudinal, integrated pharmacy course.Methods. A one-credit course, Applications of Pharmacy Practice, was built into a revised curriculum. The course was offered during the first six semesters of the Doctor of Pharmacy curriculum and met once every three weeks for a total of five sessions per semester. Each session integrated curricular material from all courses taught during a given semester into an individual, case-based assessment and a team activity. Team activities were evaluated using rubrics developed based on the Core Entrustable Professional Activities for New Pharmacy Graduates.Results. First-year students were automatically enrolled in the inaugural offerings of the course in fall 2018 and spring 2019, and the majority of students achieved final course grades of 70% to 89% for each semester. Students reported that the course helped them to develop critical-thinking skills and to keep up with semester material. Although the majority of students believed the addition of the course to the curriculum was beneficial, some felt the expectation for them to keep up with all course material was excessive.Conclusion. The addition of a longitudinal integrated course, Applications of Pharmacy Practice, appeared to benefit students, helping them integrate material from all of their courses during the semester. This integration of clinical, administrative, and pharmaceutical sciences material reduced compartmentalization of knowledge. Future studies should investigate the impact of this course on student success and performance on standardized assessments.

Cellular uptake and cytotoxicity studies of pH-responsive polymeric nanoparticles fabricated by dispersion polymerization.

OBJECTIVE: A strategy in site-specific drug delivery is the use of pH-gradients that exist in diseased conditions such as cancer for the release of loaded drug(s) in the biophase. The objective of this work is to synthesize pH-responsive docetaxel-loaded nanoparticles with a bisacrylate acetal crosslinker, which can get internalized into cells, and which will be equivalent to or more cytotoxic than the free drug against cancer cells. METHODS: pH-responsive nanoparticles were synthesized by a dispersion polymerization technique. The nanoparticles were characterized for physicochemical properties. Cytotoxicity studies of the nanoparticles were performed on PC3 and LNCaP prostate cancer cell lines using a cell viability assay. Cellular uptake studies were performed using a confocal laser scanning microscope. RESULTS: Smooth spherical nanoparticles were formed. In-vitro drug release was faster at pH 5.0 than pH 7.4, which confirmed the pH-responsiveness of the nanoparticles. Cytotoxicity studies showed that the nanoparticles were more effective at the same molar amount than the free drug against cancer cells. Both dose exposure and incubation time affected the cytotoxicity of prostate cancer cells. Furthermore, LNCaP cells appeared to be the more sensitive to docetaxel than PC3 cells. The cellular uptake studies clearly showed the presence of discrete nanoparticles within the cells in as little as 2 hours. CONCLUSION: pH-sensitive nanoparticles were developed; they degraded quickly in the mildly acidic environments similar to those found in endosomes and lysosomes of tumor tissues. These novel pH-sensitive nanoparticles would offer several advantages over conventional drug therapies.

Antiretroviral Drugs-Loaded Nanoparticles Fabricated by Dispersion Polymerization with Potential for HIV/AIDS Treatment.

Highly active antiretroviral (ARV) therapy (HAART) for chronic suppression of HIV replication has revolutionized the treatment of HIV/AIDS. HAART is no panacea; treatments must be maintained for life. Although great progress has been made in ARV therapy, HIV continues to replicate in anatomical and intracellular sites where ARV drugs have restricted access. Nanotechnology has been considered a platform to circumvent some of the challenges in HIV/AIDS treatment. Dispersion polymerization was used to fabricate two types (PMM and ECA) of polymeric nanoparticles, and each was successfully loaded with four ARV drugs (zidovudine, lamivudine, nevirapine, and raltegravir), followed by physicochemical characterization: scanning electron microscope, particle size, zeta potential, drug loading, and in vitro availability. These nanoparticles efficiently inhibited HIV-1 infection in CEM T cells and peripheral blood mononuclear cells; they hold promise for the treatment of HIV/AIDS. The ARV-loaded nanoparticles with polyethylene glycol on the corona may facilitate tethering ligands for targeting specific receptors expressed on the cells of HIV reservoirs.

Computer Optimization of Biodegradable Nanoparticles Fabricated by Dispersion Polymerization.

Quality by design (QbD) in the pharmaceutical industry involves designing and developing drug formulations and manufacturing processes which ensure predefined drug product specifications. QbD helps to understand how process and formulation variables affect product characteristics and subsequent optimization of these variables vis-à-vis final specifications. Statistical design of experiments (DoE) identifies important parameters in a pharmaceutical dosage form design followed by optimizing the parameters with respect to certain specifications. DoE establishes in mathematical form the relationships between critical process parameters together with critical material attributes and critical quality attributes. We focused on the fabrication of biodegradable nanoparticles by dispersion polymerization. Aided by a statistical software, d-optimal mixture design was used to vary the components (crosslinker, initiator, stabilizer, and macromonomers) to obtain twenty nanoparticle formulations (PLLA-based nanoparticles) and thirty formulations (poly-ɛ-caprolactone-based nanoparticles). Scheffe polynomial models were generated to predict particle size (nm), zeta potential, and yield (%) as functions of the composition of the formulations. Simultaneous optimizations were carried out on the response variables. Solutions were returned from simultaneous optimization of the response variables for component combinations to (1) minimize nanoparticle size; (2) maximize the surface negative zeta potential; and (3) maximize percent yield to make the nanoparticle fabrication an economic proposition.

Nanotechnology Approaches for the Delivery of Exogenous siRNA for HIV Therapy.

RNA interference (RNAi) is triggered by oligonucleotides that are about 21-23 nucleotides long and are capable of inducing the destruction of complementary mRNA. The RNAi technique has been successfully utilized to target HIV replication; however, the main limitation to the successful utilization of this technique in vivo is the inability of naked siRNA to cross the cell membrane by diffusion due to its strong anionic charge and large molecular weight. This review describes current nonviral nanotechnological approaches to deliver anti-HIV siRNAs for the treatment of HIV infection.

Polylactide-based paclitaxel-loaded nanoparticles fabricated by dispersion polymerization: characterization, evaluation in cancer cell lines, and preliminary biodistribution studies.

The macromonomer method was used to prepare cross-linked, paclitaxel-loaded polylactide (PLA)-polyethylene glycol (stealth) nanoparticles using free-radical dispersion polymerization. The method can facilitate the attachment of other molecules to the nanoparticle surface to make it multifunctional. Proton nuclear magnetic resonance and Fourier transform infrared spectra confirm the synthesis of PLA macromonomer and cross-linking agent. The formation of stealth nanoparticles was confirmed by scanning and transmission electron microscopy. The drug release isotherm of paclitaxel-loaded nanoparticles shows that the encapsulated drug is released over 7 days. In vitro cytotoxicity assay in selected breast and ovarian cancer cell lines reveal that the blank nanoparticle is biocompatible compared with medium-only treated controls. In addition, the paclitaxel-loaded nanoparticles exhibit similar cytotoxicity compared with paclitaxel in solution. Confocal microscopy reveals that the nanoparticles are internalized by MCF-7 breast cancer cells within 1 h. Preliminary biodistribution studies also show nanoparticle accumulation in tumor xenograft model. The nanoparticles are suitable for the controlled delivery of bioactive agents.

Optimization of the fabrication of novel stealth PLA-based nanoparticles by dispersion polymerization using D-optimal mixture design.

PURPOSE: Nanoparticle size is important in drug delivery. Clearance of nanoparticles by cells of the reticuloendothelial system has been reported to increase with increase in particle size. Further, nanoparticles should be small enough to avoid lung or spleen filtering effects. Endocytosis and accumulation in tumor tissue by the enhanced permeability and retention effect are also processes that are influenced by particle size. We present the results of studies designed to optimize cross-linked biodegradable stealth polymeric nanoparticles fabricated by dispersion polymerization. METHODS: Nanoparticles were fabricated using different amounts of macromonomer, initiators, crosslinking agent and stabilizer in a dioxane/DMSO/water solvent system. Confirmation of nanoparticle formation was by scanning electron microscopy (SEM). Particle size was measured by dynamic light scattering (DLS). D-optimal mixture statistical experimental design was used for the experimental runs, followed by model generation (Scheffe polynomial) and optimization with the aid of a computer software. Model verification was done by comparing particle size data of some suggested solutions to the predicted particle sizes. RESULTS AND CONCLUSION: Data showed that average particle sizes follow the same trend as predicted by the model. Negative terms in the model corresponding to the cross-linking agent and stabilizer indicate the important factors for minimizing particle size.

African mistletoes (Loranthaceae); ethnopharmacology, chemistry and medicinal values: an update.

Mistletoes of the Loranthaceae and Viscaceae are hemiparasitic plants and their preparations in the form of injectable extracts, infusions, tinctures, fluid extracts or tea bags are widely used in various cultures in almost every continent to treat or manage various health problems including hypertension, diabetes mellitus, inflammatory conditions, irregular menstruations, menopause, epilepsy, arthritis, cancer, etc. The medicinal values of some species of Mistletoes (Loranthaceae) growing in the West African sub-region have been reviewed along with some considerations of their chemistries and local uses. These have been compared with Mistletoes (Loranthaceae and Viscaceae) growing elsewhere in Europe and Asia. This review has attempted to update our knowledge on the values of these hemi-parasites which belong to the genera - Globimetula, Phragmanthera, Agelanthus and Tapinanthus, and which have, for years, been seen as only devastating and notorious plants. They are also seen as epiphyting economic, ornamental and medicinal plants. The hemi-parasitic plants (Mistletoes) are not well understood as very little is known about their biology (taxonomy, host/plant relationship, ecology, toxicology, physiological characteristics, etc.) and chemistry (chemical constituents' profile). Some pharmacological studies carried out on the various crude alcoholic extracts and purified fractions have, however, revealed that mistletoes showed hypotensive, hypoglycaemic, antilipidaemic, anti-oxidative, anti-inflammatory, antimicrobial, etc. effects and were non-toxic in experimental animals at the doses used. The findings showed that mistletoes can be very useful as medicinal agents in ameliorating health problems such as diabetes mellitus, hypertension, arthritis, pain, cancer and a host of other ailments if properly studied and developed.

Antibacterial activity of aqueous extracts of selected chewing sticks.

This aim of this study was to determine the antibacterial activity in extracts obtained from various Nigerian chewing sticks. Aqueous extracts from seventeen chewing sticks and the fruit of C. ferruginea, one fruit used in oral hygiene in Nigeria, were screened for antibacterial activity against type cultures of Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. Eleven of the test extracts showed activity against at least two of these referenced organisms. Minimum inhibitory concentrations (MIC) of these eleven extracts against clinical isolates from orofacial infection were determined. All the extracts demonstrated activity against Staphylococcal and Streptococcal isolates. Over half of the extracts were active against Enterobacteriaceae and obligate anaerobic isolates, including Prevotella melaninogenica, Porphyromonas gigivalis, Fusobacterium nucleatum, and Peptostreptococcus prevotii. Extracts of the Vitellaria paradoxa root, Bridellia ferruginea stem and twigs, Garcinia cola stem, Terminalia glaucescens root, Morinda lucida root, and Cnestis ferruginea fruit showed appreciable activity against all classes of bacterial isolates. The extracts of these plants may serve as sources for chemotherapeutic agents for the management of orofacial infections.