Anti-Cancer Nanotherapy: Targeted Potent Conjugated BRAF/MEK Inhibitors
In the last decade, deep understanding of key oncogenes and signaling pathways, involved in cancer pathogenesis and progression were achieved, leading to new treatment options. However, the number of patients with metastatic melanoma continue to rise. This may be attributed to the prolonged life-span of cancer patients with primary tumors, enabling metastatic spread later on. The majority of melanoma tumors found to bear a mutation in BRAF gene. This mutation causes the constitutive activation of B-Raf enzyme, which plays a role in the regulation of cell growth, thus leading to uncontrolled cell proliferation. Precise and simultaneous inhibition of B-Raf and MEK enzymes as a therapeutic approach were lately developed and showed promising results in BRAF-mutated metastatic melanoma patients
Targeted therapy as B-Raf/MEK inhibition is an efficient approach to fight cancer in a precise manner; however, it still faces challenges associated with conventional chemotherapy such as limited therapeutic response, adverse effects and acquired resistance. A more accurate and effective delivery method is required in order to target the drugs selectively and simultaneously to the tumor.
A novel targeted nanosystem, which combines on one delivery platform BRAF and MEK inhibitors with synergistic activity following simultaneous release by cathepsins, leading to increased treatment efficacy, safety, reduced side effects and prolonged tumor growth inhibition.
Our novel BRAF/MEK inhibitors nanomedicine of PGA-SLM-mDBF is synthesized by a simple and scalable “one-pot” preparation and purification
Cancer, Metastatic cancer, Melanoma
In Vitro and In Vivo data.
Polymeric Conjugates and Uses Thereof: WO2017145164
Pisarevsky E, Blau R, Epshtein Y, Ben-Shushan D, Eldar-Boock A, Tiram G, Koshrovski-Michael S, Scomparin A, Pozzi S, Krivitsky A, Shenbach-Koltin G, Yeini E, Fridrich L, White R, Satchi-Fainaro R. Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs Targeting Mutated BRAF and MEK in Melanoma. Advanced Therapeutics, https://doi.org/10.1002/adtp.202000028, 2020
checkpoint inhibitors, without inducing side effects (Fig. 2).
Figure 1. Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of free drugs. A. PGA-SLM-mDBF chemical structure. B. Preferred drugs accumulation in D4M.3A tumors in vivo following treatment with PGA-SLM-mDBF conjugate in comparison with free drugs. C. Survival of mice treated with PGA-SLM-mDBF conjugate, free drugs or untreated mice (n=4-5). Statistical significance was calculated via the log-rank (Mantel–Cox) test. D. Representative images showing pMEK inhibition of D4M.3A tumor sections of mice treated with PGA-SLM-mDBF conjugate versus untreated mice. E. D4M.3A tumor growth curves during and post treatments with PGA-SLM-mDBF conjugate, free drugs and untreated controls. Data are presented as mean ± SEM (n = 4-5).
Figure 2. Anticancer efficacy: primary tumor recurrence and metastatic burden decreases post-surgical resection. A. Schematic illustration of PGA-mDBF-SLM therapy in D4M.3A melanoma mouse model of primary tumor resection and metastases induction. B. Growth curves for primary tumors in untreated and treated mice. C. Imaging of metastases spread of treated and untreated mice 10-27 days post metastases induction. D. Corresponding quantification of total photons emitted. Data are presented as mean ± SEM (n = 3-7). E. Survival of treated and untreated mice (n=3-7). Statistical significance was calculated via the log-rank (Mantel–Cox) test.