Nanoporous Gold Monolith for High Loading of Unmodified Doxorubicin and Sustained Co-Release of Doxorubicin-Rapamycin

Abstract

Nanoparticles (NPs) have been widely explored for delivering doxorubicin (DOX), an anticancer drug, to minimize cardiotoxicity. However, their efficiency is marred by a necessity to chemically modify DOX, NPs, or both and low deposition of the administered NPs on tumors. Therefore, alternative strategies should be developed to improve therapeutic efficacy and decrease toxicity. Here we report the possibility of employing a monolithic nanoporous gold (np-Au) rod as an implant for delivering DOX. The np-Au has very high DOX encapsulation efficiency (>98%) with maximum loading of 93.4 mg cm^-3 without any chemical modification required of DOX or np-Au. We provide a plausible mechanism for the high loading of DOX in np-Au. The DOX sustained release for 26 days from np-Au in different pH conditions at 37 °C, which was monitored using UV-Vis spectroscopy. Additionally, we encased the DOX-loaded np-Au with rapamycin (RAPA)-trapped poly(D,L-lactide-co-glycolide) (PLGA) to fabricate an np-Au@PLGA/RAPA implant and optimized the combinatorial release of DOX and RAPA. Further exploiting the effect of the protein corona around np-Au and np-Au@PLGA/RAPA showed zero-order release kinetics of DOX. This work proves that the np-Au-based implant has the potential to be used as a DOX carrier of potential use in cancer treatment.

Keywords: doxorubicin; implant; nanoporous gold; rapamycin; sustained drug release.

Scheme 1

(A) Illustration of the fabrication of DOX-loaded np-Au@PLGA/RAPA implant and sustained release of drugs from as-prepared system and (B) the chemical structures of DOX, RAPA, and PLGA.

Figure 1

Cyclic voltammogram (CV) of the Au electrode (black) and np-Au millirod placed on the Au electrode (red); insets (i) is a photographic image of alloy and np-Au millirod (length = 5 mm) and (ii) is the magnified CV of the Au electrode.

Figure 2

SEM images of top view (A,A’) and cross-sectional view (B,B’) of np-Au millirod at low (A,B) and high (A’,B’) magnifications. Letters a and b in figure (B’) represent typical ligament width and interligament gaps, respectively.

Figure 3

Size distribution of ligament width (A,B) and interligament gap (A’,B’) of the top or exterior (A,A’) and cross-sectional or interior (B,B’) regions of np-Au.

Figure 4

Typical EDX spectra of alloy (top) and the np-Au (bottom) showing removal of reactive metals present in the alloy after dealloying process.

Figure 5

Loading of DOX inside np-Au from low concentration (25 µM) solution at a different pH environment with or without 0.14 M NaCl.

Figure 6

Loading of different volumes of 1 mM DOX on np-Au at pH 5.5. (A) Photographic image of original DOX (left) and after 24 h loading on np-Au from 0.1, 0.2, and 0.3 mL DOX solution. (B) Amount of DOX loaded on np-Au from a different volume.

Figure 7

Typical atomic force microscopy (AFM) topographic images of np-Au before (A) and after DOX loading (B) and their corresponding 3D view and height distribution profiles on the right.

Figure 8

FTIR-ATR spectra of solid samples of pure DOX (blue) and DOX extracted from np-Au by DMSO (red).

Scheme 2

Proposed mechanism of DOX loading on np-Au from high and low concentrations and release conditions.

Figure 9

Electrostatic potential surface of HOMO and LUMO of DOX in the front and side view.

Figure 10

SEM image showing cross-section of np-Au@PLGA/RAPA obtained by single dip coating. The thickness of PLGA coating is ≈1.5 µm. Scale bar:10 µm.

Figure 11

Cumulative release of drugs as a function of time. (A) DOX from np-Au in buffers at different pH, (B) and (C) DOX and RAPA, respectively, from np-Au@PLGA/RAPA in buffers at different pH, and (D) DOX from np-Au and np-Au@PLGA/RAPA in newborn calf serum (NBCS) at pH 7.4.