Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy.

This study reports on the design and synthesis of hypoxia responsive nanoparticles (HRNPs) composed of methoxy polyethylene glycol-4,4 dicarboxylic azolinker-chitosan (mPEG-Azo-chitosan) as ideal drug delivery platform for Fingolimod (FTY720, F) delivery to achieve selective and highly enhanced TNBC therapy in vivo. Herein, HRNPs with an average size of 49.86 nm and a zeta potential of +3.22 mV were synthetized, which after PEG shedding can shift into a more positively-charged NPs (+30.3 mV), possessing self-activation ability under hypoxia situation in vitro, 2D and 3D culture. Treatment with lower doses of HRNPs@F significantly reduced MDA-MB-231 microtumor size to 15 %, induced apoptosis by 88 % within 72 h and reduced highly-proliferative 4 T1 tumor weight by 87.66 % vs. ∼30 % for Fingolimod compared to the untreated controls. To the best of our knowledge, this is the first record for development of hypoxia-responsive chitosan-based NPs with desirable physicochemical properties, and selective self-activation potential to generate highly-charged nanosized tumor-penetrating chitosan NPs. This formulation is capable of localized delivery of Fingolimod to the tumor core, minimizing its side effects while boosting its anti-tumor potential for eradication of TNBC solid tumors.

Prospects for hypoxia-based drug delivery platforms for the elimination of advanced metastatic tumors: From 3D modeling to clinical concepts.

Hypoxia is a unique characteristic of the solid tumor microenvironment. Hypoxia contributes to multi-drug resistance, metastasis and cancer relapse through numerous molecular pathways, but at the same time provides an opportunity for the development of novel drugs or modalities specifically targeting hypoxic tumor regions. Given the high significance of tumor hypoxia in therapeutic results, we here discuss a variety of hypoxia-adopted strategies, and their potential and utility in the treatment of deep-seated hypoxic tumor cells. We discuss the merits and demerits of these approaches, as well as their combination with other approaches such as photodynamic therapy. We also survey the currently available 3D hypoxia modeling systems, in particular organoid-based microfluidics. Finally, we discuss the potential and the current status of preclinical tumor hypoxia approaches in clinical trials for advanced cancer. We believe that multi-modal imaging and therapeutic hypoxia adopted drug delivery platforms could provide better efficacy and safety profiles, and more importantly personalized therapy. Determining the hypoxia status of tumors could offer a second chance for the clinical translation of hypoxia-based agents, such as hypoxia activated prodrugs (HAPs) from bench to bedside.

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release, targeted drug delivery, post-surgery implants (immunovaccines), theranostics, biosensing of tumor-derived circulating materials, multimodal systems, and combination therapy platforms with the potential to eliminate bulk tumors as well as lingering tumor cells to treat minimal residual disease (MRD) and recurrent cancer. We first introduce different formats, derivatives, and properties of chitosan. Next, given the barriers to therapeutic efficacy in solid tumors, we review advanced formulations of chitosan modules as efficient drug delivery systems to overcome tumor heterogeneity, multi-drug resistance, MRD, and metastasis. Finally, we discuss chitosan NPs for clinical translation and treatment of recurrent cancer and their future perspective.

Phenotypic and Molecular Epidemiology of Acinetobacter calcoaceticus baumannii Complex Strains Spread at Nemazee Hospital of Shiraz, Iran.

BACKGROUND: Acinetobacter calcoaceticus baumannii (ACB) complex are Gram-negative opportunistic bacteria with low virulence properties. Their resistance to antibiotics has become a matter of concern in hospital infections. OBJECTIVES: The present study aimed to determine the prevalence and antimicrobial susceptibility of ACB isolates collected from the Nemazee hospital of Shiraz. In addition, Pulsed Field Gel Electrophoresis (PFGE) was used to determine the genetic patterns of these strains. PATIENTS AND METHODS: In this cross-sectional study, 93 strains of ACB complex were isolated from patients of Nemazee hospital, Shiraz, Iran. The antibiotic susceptibility patterns of the isolates to the following 15 antibiotics were determined: gentamicin, ticarcillin, ceftazidime, co-trimoxazole, imipenem, piperacillin tazobactam, amikacin, aztreonam, sulbactam, meropenem, tobramycin, cefotaxime, ceftriaxone, colistin, polymyxin B. Pulsed Field Gel Electrophoresis was used to determine the clonal relationship of these strains. RESULTS: Most of the isolates were found to be resistant to cefotaxime, co-trimoxazole, ceftriaxone, aztreonam, ceftazidime and ticarcillin (90%), and the least resistance was observed to colistin and polymyxin B. Among the 93 tested samples, 35 antimicrobial susceptibility patterns and 47 PFGE patterns were obtained. CONCLUSIONS: High resistance to antibiotics was observed among the strains of ACB complex and the least resistance was towards colistin and polymyxin B, indicating that these antibiotics could be effective for treatment, in case there is no other choice. Using PFGE, the similarity between some strains of Acinetobacter was determined, which indicated epidemics in different parts of the hospital; such epidemics can in turn lead to increased incidence of Acinetobacter infections.