Single Polymer-drug Conjugate Carrying Two Drugs for Fixed-dose Co-delivery

Due to molecular complexity of many diseases, co-delivery of multiple therapeutic cargos aiming at various targets and displaying different toxicity profiles within the same carrier is becoming increasingly important for enhancing the therapeutic efficacy, overcoming drug resistance, reducing the dose of each agent and reducing side effects [1-4]. A various carriers including liposomes, polymeric micelles, PLGA nanoparticles, dendrimers, mesoporous silica nanoparticles, Janus particles and DNA nanogels have all been adapted for co-delivery [2,4]. Among which, the dual drug loaded polymer micelles usually can be formed via four different ways [5-7]: (1) polymer plus two kinds of free drugs: drugs are loaded during the self-assembly process by including them in the solvent with the polymer. (2) polymer–drug conjugate plus free drug: in this approach a polymer–drug conjugate is formed first, followed by self-assembly and encapsulation of the free drug. (3) Polymer–drug conjugate plus polymer–drug conjugate: two polymer–drug conjugates, each with a single type of drugs, are administered in combination. (4) Single polymer–drug conjugate carrying a combination of drugs: the formation of a chemically mixed micelle containing both types of drugs conjugated to a single polymer. The last two approaches are considered to be promising for fixeddose combination therapy purpose which can direct the system to be synergistic, additive or antagonistic [8,9]. For polymer–drug conjugate plus polymer–drug conjugate, the two populations of conjugates can be mixed in a given ratio to obtain micelles containing a determined ratio of two drugs. While for single polymer-drug conjugate carrying a combination of drugs, more precisely and convenient ratiometric control between the two drugs could be obtained in the initial chemical synthesis process. Also type 4 is the only approach that can guarantee simultaneous delivery of both drugs to the same site of action, and with careful design, can enable synergistic drug effects [10,11]. However, the main obstacle that we would encounter is the difficulty of attaching two different drugs to the same polymer backbone at a controlled fashion.