Temozolomide Release Research Articles

A novel biocompatible drug delivery system of chitosan/temozolomide nanoparticles loaded PCL-PU nanofibers for sustained delivery of temozolomide

In the present study, the anticancer drug temozolomide (TMZ) was initially loaded into the chitosan (CS) nanoparticles and synthesized CS/TMZ nanoparticles were incorporated into the synthesized poly (ε-caprolactone diol) based polyurethane (PCL-Diol-b-PU) nanofibers. The synthesized nanoparticles and nanofibers were characterized using dynamic light scattering, transmission electron microscopy, X-ray powder diffraction and scanning electron microscopy. The obtained results revealed that the CS/TMZ nanoparticles were successfully embedded into the PCL-Diol-b-PU nanofibers. The gold nanoparticles with average particle size of 18nm were synthesized and coated on the nanofibers surface to enhance the antitumor activity of CS/TMZ loaded nanofibers against inhibiting the growth of U-87 MG human glioblastoma cells. The sustained TMZ release for 30days with the zero order kinetic model were achieved from both CS/TMZ loaded PCL-Diol-b-PU and gold-coated nanofibers. The cell viability results indicated that the gold-coated nanofibers can effectively inhibit the growth of U-87 glioblastoma cells. Therefore, the prepared gold-coated CS/TMZ loaded PCL-Diol-b-PU nanofibers would be a potential candidate for glioblastoma cancer treatment.

A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin.

The development of effective therapeutic strategies for glioblastoma faces challenges such as modulating the blood brain barrier (BBB) for drug influx and selectively targeting tumor cells. Nanocarrier drug delivery strategies are functionalized to enhance vascular permeability. We engineered superparamagnetic iron oxide nanoparticle (SPION) based polymeric nanocomposites (84.37 ± 12.37 nm / 101.56 ± 7.42 nm) embedding temozolomide (TMZ) targeted against glioblastoma by tagging an antibody against nestin, a stem cell marker, and transferrin / polysorbate-80 to permeate the BBB. The targeting and therapeutic efficacy of the nanocomposite resulted in enhanced permeability across the BBB in an orthotopic glioblastoma xenograft model. Sustained release of TMZ from the nanocomposite contributed to enhanced tumor cell death while sparing normal brain cells as evidenced through micro SPECT/CT analysis. The functionalized nanocomposites showed significant reductions in tumor volume compared to pure TMZ, as substantiated by reduced proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67. We report here a novel targeted TMZ delivery strategy using a potent homing moiety, nestin, tagged to a polymeric nanocomposite to target glioblastoma. In addition to tumor targeting, this study constitutes a broad horizon for enhanced therapeutic efficacy with further scope for capitalizing on the magnetic properties of SPION for targeted killing of cancer cells while sparing normal tissues.

Temozolomide-loaded photopolymerizable PEG-DMA-based hydrogel for the treatment of glioblastoma

Glioblastoma is the most frequent primary malignant brain tumor in adults. Despite treatments including surgery, radiotherapy and chemotherapy by oral Temozolomide (TMZ), the prognosis of patients with glioblastoma remains very poor. We hypothesized that a polyethylene glycol dimethacrylate (PEG-DMA) injectable hydrogel would provide a sustained and local delivery of TMZ. The hydrogel photopolymerized rapidly (<2min) and presented a viscous modulus (≈10kPa). TMZ release kinetic presented two phases: a linear burst release of 45% of TMZ during the first 24h, followed by a logarithmic release of 20% over the first week. The in vivo tolerability study showed that the unloaded hydrogel did not induce apoptosis in mice brains nor increased microglial activation. In vivo, the anti-tumor efficacy of TMZ-hydrogel was evaluated on xenograft U87MG tumor-bearing nude mice. The tumor weight of mice treated with the photopolymerized TMZ hydrogel drastically decreased compared with all other groups. Higher apoptosis (located at the center of the tumor) was also observed. The present study demonstrates the potential of a photopolymerizable TMZ-loaded hydrogel to treat glioblastoma.

Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in vitro. The safety of implanting the device intracranially was confirmed with preliminary in vivo studies. The impact of TMZ release kinetics was investigated by conducting in vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.