Temozolomide Delivery to Tumor Cells by a Multifunctional Nano Vehicle Based on Poly(β-L-malic acid)

Abstract

Purpose Temozolomide (TMZ) is a pro-drug releasing a DNA alkylating agent that is the most effective drug to treat glial tumors when combined with radiation. TMZ is toxic, and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity. Methods Multifunctional targetable nanoconjugates of TMZ hydrazide were synthesized using poly(β-L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL), for pH-dependent endosomal membrane disruption, and PEG for protection. Results The water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and ζ potentials in the range of −6.3 to −17.7 mV. Fifty percent degradation in human plasma was observed in 40 h at 37°C. TMZ conjugated with polymer had a half-life of 5–7 h, compared with 1.8 h for free TMZ. The strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody. TMZ-resistant cancer cell lines were sensitive to TMZ nanoconjugate treatment. Conclusions TMZ-polymer nanoconjugates entered the tumor cells by receptor-mediated endocytosis, effectively reduced cancer cell viability, and can potentially be used for targeted tumor treatment.

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…6. The greater drug accumulation was due to the avoidance of the drug efflux pump mechanism via receptor-mediated endocytosis [111]. In addition to T98G, the human glioblastoma cell line U251 is known to have MDR due to the high expression of P-glycoprotein and other ABC transporters.…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…56,57 Studies have shown that nanomedicines can overcome tumor chemoresistance to alkylating agents. [58][59][60] For example, temozolomide, a commonly used alkylating agent, is considered the gold standard for the treatment of glioblastoma. 61,62 However, growing resistance to temozolomide remains a major clinical challenge.…”

“…60,65,66 Patil et al synthesized multifunctional temozolomide nanoconjugates (6.5-14.8 nm) using poly(β-l-malic acid), which contained trileucine (LLL) and antibody to transferrin receptor. 58 It was found that temozolomide-resistant cells were sensitive to the temozolomide nanoconjugates, 58 clearly demonstrating the feasibility of overcoming tumor cell resistance to the alkylating agent temozolomide by formulating it into nanomedicine.…”

Biocompatible Nanopolymers: The Next Generation of Breast Cancer Treatment?

“…The multifunctionality of nanopolymers bearing various antisense oligonucleotides has been demonstrated by highly efficient treatment of glioblastoma [11], HER2 + [12] and triple- negative [13] breast tumors in vivo, and with temozolomide treatment of brain cancer cells in vitro [14]. …”