Protein Nanocapsules Containing Doxorubicin as a pH‐Responsive Delivery System

Abstract

The E2 component of pyruvate dehydrogenase has been engineered to form a caged, hollow dodecahedral protein assembly, and we have examined the feasibility of this scaffold to be used as a drug delivery system by introducing cysteines to the internal cavity (D381C). Fluorescent dye Alexa Fluor 532 (AF532M) and the antitumor drug doxorubicin were coupled to this internal cavity through maleimides on the guest molecules. The virus-like particle’s structure and stability remained intact after binding of the molecules within the interior of the nanocapsule. The pH-dependent hydrolysis of a hydrazone linkage to doxorubicin allowed 90% drug release from the D381C scaffold within 72 hrs at pH 5.0. Fluorescence microscopy of MDA-MB-231 breast cancer cells indicated significant uptake of the D381C scaffold incorporating AF532M and doxorubicin and suggested internalization of the nanoparticles through endocytosis. We observed that the protein scaffold does not induce cell death, but doxorubicin encapsulated in D381C is indeed cytotoxic, yielding an IC50 of 1.3 ± 0.3 μM. While the majority of particulate-based drug delivery strategies encapsulates drugs within polymeric nanoparticles, our results show the potential of using macromolecular protein assemblies. This approach yields a promising new opportunity for designing highly-defined nanomaterials for therapeutic delivery.

High drug-loading nanomedicines: progress, current status, and prospects

“…121 Hydrophobic drug molecules, peptides, and gene drugs are covalently conjugated to the hollow cavity of the protein scaffold or noncovalently loaded into the internal space. [122][123][124][125] Generally, restricted by the number of attachment sites, most of the protein NP-based nanomedicines prepared by conventional chemical conjugation present the same drawback of lower drug-loading content (,10%). 122 One feasible way to enhance the drug-loading capacity of protein nanocarriers is designing and increasing the hydrophobic surface area of the protein NP.…”

“…122 One feasible way to enhance the drug-loading capacity of protein nanocarriers is designing and increasing the hydrophobic surface area of the protein NP. Inspired by transport mechanism of multidrug-efflux transporters, 126 Ren et al 123 implemented a biomimetic approach to enhance hydrophobic drug-protein interactions. Several virus-like protein NPs were redesigned and prepared via self-assembly of the E 2 component of the pyruvate dehydrogenase multienzyme complex.…”

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

“…In fact, different intracellular concentrations and locations (nucleus or cytoplasm) have been reported when DOX is loaded within/on the surface of the NPs compared with the concentrations attained when using free DOX-this has been attributed to a simple diffusion or endocytosis process. 45,46 Free DOX and DOX-loaded NPs predominantly situated themselves within the nucleus of both MCF7 and E0771 cells. However, when the antitumor drug was loaded in NPs, DOX also accumulated in the cytoplasm after a short period of exposure.…”

Present and Future Application of Nanoparticle Based Therapies in B-Chronic Lymphocytic Leukemia (B-CLL)

“…This could also be true for many other old onco-hematologic chemo-therapeutic agents with a fairly interesting efficacy and safety profile that could be re-discovered for their use in B-CLL and other leukemias and lymphomas by delivering them in nanoparticles. This could be the case of doxorubicin or tamoxifene (15,16), or even bendamustine. This last drug has been used for more than 30 years in the treatment of lymphoma, but little is known about the optimal dosing schedule in relapsed or refractory B-cell chronic lymphocytic leukemia (CLL).…”