Traceable Multifunctional Micellar Nanocarriers for Cancer-Targeted Co-delivery of MDR-1 siRNA and Doxorubicin

Abstract

In this article we report on the development of polymeric micelles that can integrate multiple functions in one system, including the capability to accommodate a combination of therapeutic entities with different physicochemical properties (i.e., siRNA and doxorubicin; DOX), passive and active cancer targeting, cell membrane translocation, and pH-triggered drug release. A micellar system was constructed from degradable poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with functional groups on both blocks. The functional group on the PCL block was used to incorporate short polyamines for complexation with siRNA or to chemically conjugate DOX via a pH-sensitive hydrazone linkage. A virus mimetic shell was conferred by attaching two ligands, i.e., the integrin αvβ3-specific ligand (RGD4C) for active cancer targeting and the cell-penetrating peptide TAT for membrane activity. This system was used to improve the efficacy of DOX in multidrug-resistant MDA-MB-435 human tumor models that overexpress P-glycoprotein (P-gp), by simultaneous intracellular delivery of DOX and siRNA against P-gp expression. The carrier was tagged with near-infrared fluorescent imaging probes to provide a means to follow the fate of the system in vivo upon intravenous administration. Dy677-labeled siRNA was also used to assess the in vivo stability of the siRNA carrier. This multifunctional polymeric micellar system was shown to be capable of DOX and siRNA delivery to their intracellular targets, leading to the inhibition of P-gp-mediated DOX resistance in vitro and targeting of αvβ3-positive tumors in vivo.

Nanocarriers for siRNA delivery to overcome cancer multidrug resistance

“…Some polymers, such as -cyclodextrin, PEO-block-poly (-caprolactone) (PCL) and dextran, which do not contain amino groups in their chemical structures, can also deliver siRNA after appropriate modification [88][89][90][91][92]. Li et al [88] developed a MDR1 siRNA and Dox co-delivery system, in which CdSe/ZnSe quantum dots were coated with -cyclodextrin via amino acids L-Arg or L-His.…”

“…With the help of -carboxyl groups, one can endow the PCL polymer with more functionality, including the abilities to deliver nuclear acid drug. Xiong et al [89,90] modified PEO-PCCL with spermine or N,Ndimethyldipropylenetriamine. Amino groups introduced in its structures bound siRNA stably via electrostatic attraction under physiological conditions.…”

“…The PEO blocks were able to be decorated with integrin v3 targeting peptide (RGD4C) and/or cell penetrating peptide (TAT), increasing the specificity to MDR cancer cells. Dox was further conjugated to PEO-PCCL via pH-sensitive hydrazone bond forming a codelivery system of Dox and MDR1 siRNA [90]. This system significantly increased cellular uptake, improved Dox penetration into nuclei, and finally enhanced Dox cytotoxicity in Dox-resistant MDA-MB-435 cancer models.…”

Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different kinds of anticancer drugs

“…For example, it has been demonstrated that combining a chemotherapeutic agent with siRNA in a co-delivery nanocarrier can significantly enhance therapeutic efficacy. [20][21][22][23] In the past few decades, many efforts have been made to improve the solubility, stability, and pharmacokinetics of small molecule organic drugs with the aid of cyclodextrins (CDs) and their derivatives. The hydrophobic internal cavity of CDs endows them with the capability to form inclusion complexes with organic drugs, and their hydrophilic exterior (due to the presence of hydroxyl radicals) guarantees good water solubility of the complexes.…”

Redox-responsive core cross-linked prodrug micelles prepared by click chemistry for pH-triggered doxorubicin delivery

“…Indeed, polymeric prodrugs can overcome inherent drawbacks of drug such as poor water solubility, chemical instability, and rapid metabolism. There are many routes for preparation of polymeric prodrugs which showed high drug loading efficiency [19,20]. They can be prepared by preformed polymers [21,22], polymerization reaction of drug-bearing monomers [23][24][25], or ring-opening polymerization of a druginitiator [26,27].…”