Background: The combination of two or more therapeutic drugs is an attractive approach
to improve the treatment of experimental tumors. Leveraging nanocarriers for combinational drug
delivery can allow control over drug biological fate and promote co-localization in the same area of
the body. However, there are certain concerns regarding the biodegradability and potential longterm
toxicity arising from these synthetic nanoscale carriers.
Objective: Our aim was to develop a combinational nanodrug delivery system formed by selfassembling
of amphiphilic drug moleculesminimizing potential toxicities associated with using
additional synthetic nanocarriers.
Methods: A novel prodrug chlorambucil gemcitabine conjugate was synthesized, this prodrug was
used for the encapsulation of an additional hydrophobic anticancer drug paclitaxel, taking the form
of combinational nanodrugs. Particle size and zeta potential were evaluated, cytotoxicity assay and
apoptosis/cell cycle analysis were also performed to validate the anticancer efficacy of the combinational
Results: The combinational nanodrugs were acquired by means of nanoprecipitation. In A549 lung
adenocarcinoma cell line, cellular assays revealed that co-delivery of low dosage paclitaxel with
chlorambucil gemcitabine conjugate can act synergistically to inhibit cell growth and induce accumulation
of cells in the G2/M phase with a concomitant decrease in G0/G1 compartment.
Conclusion: Chlorambucil gemcitabine conjugate and paclitaxel can co-assemble into composite
nanoparticles by a nanoprecipitation process and the resulting combinational nanodrugs showed a
synergistic anticancer effect. This synthetic nanocarrier-free approach might broaden the nanodrug
concept and have potential in cancer therapy.