Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells.

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine.

Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells.

Purpose: Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging.

Imaging of intranasal drug delivery to the brain.

Intranasal (IN) delivery is a rapidly developing area for therapies with great potential for the treatment of central nervous system (CNS) diseases. Moreover, in vivo imaging is becoming an important part of therapy assessment, both clinically in humans and translationally in animals. IN drug delivery is an alternative to systemic administration that uses the direct anatomic pathway between the olfactory/trigeminal neuroepithelium of the nasal mucosa and the brain.

Injectable, long-acting PLGA formulations: Analyzing PLGA and understanding microparticle formation.

Injectable, long-acting depot formulations based on poly(lactide-co-glycolide) (PLGA) have been used clinically since 1989. Despite 30 years of development, however, there are only 19 different drugs in PLGA formulations approved by the U.S.

PLA micro- and nano-particles.

Poly(d,l-lactic acid) (PLA) has been widely used for various biomedical applications for its biodegradable, biocompatible, and nontoxic properties. Various methods, such as emulsion, salting out, and precipitation, have been used to make better PLA micro- and nano-particle formulations. They are widely used as controlled drug delivery systems of therapeutic molecules, including proteins, genes, vaccines, and anticancer drugs.

Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery.

As the field of biotechnology has advanced, oral protein delivery has also made significant progress. Oral delivery is the most common method of drug administration with high levels of patient acceptance. Despite the preference of oral delivery, administration of therapeutic proteins has been extremely difficult.

Continentalic acid from Aralia continentalis shows activity against methicillin-resistant Staphylococcus aureus.

In a continuing search for compounds with antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), a chloroform extract of roots of Aralia continentalis was found to contain continentalic acid (CA, C(20)H(30)O(2)), a diterpenic acid. This compound exhibited potent activity against standard methicillin-susceptible Staphylococcus aureus (MSSA) as well as clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). It was determined that continentalic acid had minimum inhibitory concentrations (MICs) of approximately 8-16 microg/mL against S.