Peptide dendrimers as potentiators of conventional chemotherapy in the treatment of pancreatic cancer in a mouse model

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal cancers, that are both least responsive to chemotherapy, and have a 5-year survival rate of less than 9%. Majority of the patients with PDAC present to the hospital in the late stages, making chemotherapy the only appropriate mode of treatment. Pancreatic ductal adenocarcinoma (PDAC) has a complex structure, where stroma (tissue surrounding the cancer cells) accounts for 80% of the tumor, leading to sparse vasculature. This limits the delivery of the drugs to the tumor, which leads to minimal or no drug reaching the cancer cells. This inadequate drug delivery leads to development of drug resistance by the tumor cells. Hence, development of innovative drug delivery systems to enhance the drug delivery is vital to improve the effectiveness of the chemotherapy and increasing the chances of survival.

To address this issue and find a better drug delivery system, scientists Sijin Huang, Xin Huang, Husheng Yan from the College of Chemistry at Nankai University designed Peptide dendrimers as an adjuvant to the chemotherapy drugs. They studied the effect of the peptide dendrimers in mice inoculated with PDAC cells. The original research article is now published in the European Journal of Pharmaceutics and Biopharmaceutics.

The authors synthesized peptide dendrimers using lysine (K) and arginine (R) residues. Generations 1, 2 and 3 of peptide dendrimers (TAEA-K₃, TAEAK₃K₆, TAEA-K₃K₆K₁₂, TAEA-K₃R₆, and TAEA-K₃K₆R₁₂, TAEA, tris(2-aminoethyl) amine, the dendrimer core) were synthesized and the effects of different generations and residues of peptide dendrimers were studied. The researchers afterward injected PDAC cells into the right flank of mice. When the tumor reached the right size, they injected the peptide dendrimers into the mice. After 30-90 minutes of peptide injection, either DOX (doxorubicin) or GEM (gemcitabine) was injected into the mice. The authors studied the effect of peptide dendrimers and biodistribution of the drugs in the tumor, heart, liver, lung, spleen, and kidneys.

The research team observed that mean tumor volume in mice injected with a combination of peptide dendrimer (TAEA-K₃K₆R₁₂) and DOX or GEM were notably reduced, compared to chemotherapy drugs alone. They also observed that there is significant reduction in the mean tumor weight in mice treated with peptide dendrimers and drugs, correlating to the reduction in the mean tumor volume. These results denote the potent effects of the dendrimers when they were administered along with chemotherapy drugs, which can be attributed to their functions of enhanced drug delivery and accumulation in cancer cells. They also demonstrated the safety profile of the dendrimers where there was no significant difference in the mean body weights of mice treated with DOX/GEM alone, DOX/GEM, and dendrimers, which denotes the low toxicity of the dendrimers. The results indicated that the mice treated with DOX/GEM and dendrimers had more dead cancer cells than the mice treated with DOX/GEM alone. They have also observed that tumor growth is completely stopped by the co-administration of peptide dendrimer (TAEA-K₃K₆R₁₂) and GEM. The histopathology reports of liver, lung, heart, spleen, and kidney indicated that dendrimers have not caused any damage to these organs. The DOX concentration in the tumor cells is threefold higher when it is administered along with peptide dendrimers than administering alone. The dendrimers did not elevate the concentration of DOX/GEM in the normal cells.

In summary, through the new study, the authors have successfully demonstrated the beneficial effects of peptide dendrimers in the treatment of PDAC. The use of nanoparticles (peptide dendrimers) can enhance the co-administered drug accumulation in and deep penetration into the tumor and uptake by cancer cells, and thereby increase the potency of the chemotherapy drugs. These results also increase the likelihood of treating PDAC with less toxic effects of chemotherapy drugs and also have better outcomes. This study further supports the potential of using peptide dendrimers in the treatment of PDAC and other tumors with complex structures and low vasculature in which it is difficult to achieve a therapeutic level of drug concentration in the tumor.