Bacillus-Shape Design of Polymer Based Drug Delivery Systems with Janus-Faced Function for Synergistic Targeted Drug Delivery and More Effective Cancer Therapy

Abstract

The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy.

Design Advances in Particulate Systems for Biomedical Applications

“…The combination of a non-spherical shape with Janus properties are related with an early phase active targeting effect and a later anticancer effect. [ 286 ] Such particles demonstrated improved targeting efficiency and antitumor activity than spherical particles with the same composition or even non-encapsulated drugs.…”

Sequence‐Defined Oligoamide Drug Conjugates of Pretubulysin and Methotrexate for Folate Receptor Targeted Cancer Therapy

“…The folate receptor (FR) is overexpressed in many types of tumors . Binding folic acid (FolA) and FolA‐derivatives with very high affinity, the FR offers a prominent approach to selectively target FR‐positive cancer cells in targeted drug delivery approaches . A clinical phase I study for the treatment of advanced solid tumors currently assesses a small molecular drug conjugate (SMDC) of FolA with tubulysin…”

“…Although the affinity of the FR toward MTX is much lower than toward FolA and the RFC is the major uptake carrier for MTX, substantial influx can also occur via the FR, overexpressed in tumor cells . Therefore, FolA and MTX can serve as targeting ligands for tumor selective therapy and facilitate the transport of FolA‐ or MTX‐derivatives into cancer cells. In contrast to FolA, MTX does not only possess ligand properties but, in its polyglutamylated form, shows increased inhibition of the enzyme dihydrofolate reductase (DHFR), which is vital in the nucleotide biosynthesis pathway, evades efflux transport mechanisms and can induce cellular impairment .…”

“…In contrast to FolA, MTX does not only possess ligand properties but, in its polyglutamylated form, shows increased inhibition of the enzyme dihydrofolate reductase (DHFR), which is vital in the nucleotide biosynthesis pathway, evades efflux transport mechanisms and can induce cellular impairment . Therefore, in FR selective drug delivery, MTX can serve both as targeting ligand and as an additional drug agent for combinatorial tumor therapy . In addition to SMDCs for FR‐targeted combination therapy, which are evaluated in this study, the nanoparticulate codelivery of MTX with various anticancer drugs has been thoroughly researched and are described in previous reports …”

“…Therefore, in FR selective drug delivery, MTX can serve both as targeting ligand and as an additional drug agent for combinatorial tumor therapy . In addition to SMDCs for FR‐targeted combination therapy, which are evaluated in this study, the nanoparticulate codelivery of MTX with various anticancer drugs has been thoroughly researched and are described in previous reports …”