Exploring temozolomide encapsulated PEGylated liposomes and lyotropic liquid crystals for effective treatment of glioblastoma: in-vitro, cell line, and pharmacokinetic studies.

Temozolomide (TMZ) is one of the best choices for treating glioblastoma. However, due to the short plasma half-life, only 20-30 % brain bioavailability can be achieved using traditional formulations. In the present study, PEGylated liposomes and lyotropic liquid crystals (LLCs) were developed and investigated to prolong the plasma circulation time of TMZ. Industrially feasible membrane extrusion and modified hot melt emulsification techniques were utilized during the formulation. Liposomes and LLCs in the particle size range of 80-120 nm were obtained with up to 50 % entrapment efficiency. The nanocarriers were found to show a prolonged release of up to 72 h. The cytotoxicity studies in glioblastoma cell lines revealed a âˆ¼1.6-fold increased cytotoxicity compared to free TMZ. PEGylated liposomes and PEGylated LLCs were found to show a 3.47 and 3.18-fold less cell uptake in macrophage cell lines than uncoated liposomes and LLCs, respectively. A 1.25 and 2-fold increase in the plasma t1/2 was observed with PEGylated liposomes and PEGylated LLCs, respectively, compared to the TMZ when administered intravenously. Extending plasma circulation time of TMZ led to significant increase in brain bioavailability. Overall, the observed improved pharmacokinetics and biodistribution of TMZ revealed the potential of these PEGylated nanocarriers in the efficient treatment of glioblastoma.

UV spectroscopic method for estimation of temozolomide: Application in stability studies in simulated plasma pH, degradation rate kinetics, formulation design, and selection of dissolution media.

Temozolomide (TMZ) is a broad spectrum alkylating agent found effective in the treatment of glioblastoma multiforme, refractory anaplastic astrocytoma, and metastatic melanoma. The major drawback associated with TMZ is pH-dependent stability and short half-life. At physiological pH, it undergoes conversion to MTIC (methyltriazine imidazole carboxamide) and AIC (amino imidazole carboxamide), resulting in only 20-30% brain bioavailability. There is a need for an analytical method for the estimation of TMZ in stability samples and nanoformulations. In this research study, analytical methods were developed for the estimation of TMZ using two media pH 1.2 (0.1 N HCl) and pH 4.5 acetate buffer, which were validated for linearity, range, precision, accuracy, limit of detection, limit of quantification, and specificity as per ICH guidelines. The % RSD was found to be <2% indicating the reliability of the method. Further, the application of the developed methods was explored. The stability of TMZ in three pH conditions (1.2, 4.5, and 7.4) and the respective degradation rate kinetics was studied. Conversion of TMZ was found to follow first order kinetics with the conversion rate of 0.0011, 0.0011, and 0.0453 h-1 in pH 1.2, 4.5, and 7.4 respectively. The developed methods accurately estimated the TMZ concentration in lipid nanoformulation (liposomes) indicated by ~100% recovery. Acetate buffer (pH 4.5) was found to be an appropriate dissolution media for TMZ loaded lipid nanoformulations. The developed methods were found to be suitable for routine analysis, for the determination of drug stability and estimation of temozolomide in lipid nanoformulations.

Evolving new-age strategies to transport therapeutics across the blood-brain-barrier.

A basic understanding of the blood-brain barrier (BBB) is essential for the novel advancements in targeting drugs specific to the brain. Neoplasm compromising the internal structure of BBB that results in impaired vasculature is called as blood tumor barrier (BTB). Besides, the BBB serves as a chief hindrance to the passage of a drug into the brain parenchyma. The small and hydrophilic drugs majorly display an absence of desired molecular characteristics required to cross the BBB. Furthermore, all classes of biologics have failed in the clinical trials of brain diseases over the past years since these biologics are large molecules that do not cross the BBB. Also, new strategies have been discovered that use the Trojan horse technology with the re-engineered biologics for BBB transport. Thus, this review delivers information about the different grades of tumors (I-IV) i.e. examples of BBB/BTB heterogenicity along with the different mechanisms for transporting the therapeutics into the brain tumors by crossing BBB. This review also provides insights into the emerging approaches of peptide delivery and the non-invasive and brain-specific molecular Trojan horse targeting technologies. Also, the several challenges in the clinical development of BBB penetrating IgG fusion protein have been discussed.