2 research outputs found
Coencapsulation of alendronate and doxorubicin in pegylated liposomes: a novel formulation for chemoimmunotherapy of cancer
<p>We developed a pegylated liposome formulation of a dissociable salt of a nitrogen-containing bisphosphonate, alendronate (Ald), coencapsulated with the anthracycline, doxorubicin (Dox), a commonly used chemotherapeutic agent. Liposome-encapsulated ammonium Ald generates a gradient driving Dox into liposomes, forming a salt that holds both drugs in the liposome water phase. The resulting formulation (PLAD) allows for a high-loading efficiency of Dox, comparable to that of clinically approved pegylated liposomal doxorubicin sulfate (PLD) and is very stable in plasma stability assays. Cytotoxicity tests indicate greater potency for PLAD compared to PLD. This appears to be related to a synergistic effect of the coencapsulated Ald and Dox. PLAD and PLD differed in <i>in vitro</i> monocyte-induced IL-1β release (greater for PLAD) and complement activation (greater for PLD). A molar ratio Ald/Dox of ∼1:1 seems to provide an optimal compromise between loading efficiency of Dox, circulation time and <i>in vivo</i> toxicity of PLAD. In mice, the circulation half-life and tumor uptake of PLAD were comparable to PLD. In the M109R and 4T1 tumor models in immunocompetent mice, PLAD was superior to PLD in the growth inhibition of subcutaneous tumor implants. This new formulation appears to be a promising tool to exploit the antitumor effects of aminobisphosphonates in synergy with chemotherapy.</p
Exploiting the Metal-Chelating Properties of the Drug Cargo for <i>In Vivo</i> Positron Emission Tomography Imaging of Liposomal Nanomedicines
The
clinical value of current and future nanomedicines can be improved
by introducing patient selection strategies based on noninvasive sensitive
whole-body imaging techniques such as positron emission tomography
(PET). Thus, a broad method to radiolabel and track preformed nanomedicines
such as liposomal drugs with PET radionuclides will have a wide impact
in nanomedicine. Here, we introduce a simple and efficient PET radiolabeling
method that exploits the metal-chelating properties of certain drugs
(<i>e.g.</i>, bisphosphonates such as alendronate and anthracyclines
such as doxorubicin) and widely used ionophores to achieve excellent
radiolabeling yields, purities, and stabilities with <sup>89</sup>Zr, <sup>52</sup>Mn, and <sup>64</sup>Cu, and without the requirement
of modification of the nanomedicine components. In a model of metastatic
breast cancer, we demonstrate that this technique allows quantification
of the biodistribution of a radiolabeled stealth liposomal nanomedicine
containing alendronate that shows high uptake in primary tumors and
metastatic organs. The versatility, efficiency, simplicity, and GMP
compatibility of this method may enable submicrodosing imaging studies
of liposomal nanomedicines containing chelating drugs in humans and
may have clinical impact by facilitating the introduction of image-guided
therapeutic strategies in current and future nanomedicine clinical
studies