Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases

Abstract

Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,L-lactide-co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumor-induced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the anti-tumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P = 0.014, P = 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.

Application of silk fibroin/chitosan/nano‑hydroxyapatite composite scaffold in the repair of rabbit radial bone defect

“…Thus, ensuring high mechanical strength in artificial scaffolds is essential. In order to repair different types of bone defects, scaffolds that are sufficiently strong and allow remodeling are required (18). Good biocompatibility with the host is essential, which refers to the absence of immune rejection risk, inflammation or even carcinogenesis following implantation.…”

PLGA-Alendronate Conjugate as a New Biomaterial to Produce Osteotropic Drug Nanocarriers

“…DOX effectiveness has been greatly improved when specific targeting at the tumour sites has been achieved, for instance by loading the drug into liposomes (e.g., Caelyx ® /Doxil ® ) [42,43]. DOX was loaded in the previously described PLGA-ALE NPs and the anti-tumour effect of the carrier was assessed in vitro and in vivo [44]. In a first instance, the intracellular accumulation and distribution of DOX-loaded NPs was assessed by fluorescence and confocal microscopy, in comparison with free DOX.…”

“…Therefore, it is likely that the observed cytoplasmic fluorescence was due to the same phenomenon, and that the DOX-loaded NPs were trafficked through the endo-lysosomal compartment. The incubation of the above cell lines with DOX-loaded PLGA-ALE NPs (48 and 72 h) gave a cell growth inhibition profile very similar to that one of the free drug [44]. To evaluate the in vivo activity, DOX-loaded NPs were injected into a mouse model of breast cancer bone metastases: osteolytic lesions were induced by intratibial inoculation of the human breast carcinoma cells MDA-MB-231 that can induce prominent bone metastases.…”

“…* P < 0.05, ** P < 0.005 (modified from ref. [44]). NPs (0.090±0.009 vs. 0.310±0.040 mm 2 , P = 0.033); both free and NP-loaded DOX reached a similar effect at the end of the experiment (day 42) (Figure 13B).…”

Nanoparticles and their potential for application in bone

“…9,10 Similarly, nanoparticle treatment of systemic bone diseases such as osteoporosis might be feasible in the future. To date, several molecules to target bone have been identified, such as bisphosphonates and their derivatives, [11][12][13] as well as oligopeptides targeting specifically bone-resorption 14 or bone-formation surfaces. 15 Summarizing, to achieve the desired effect, nanoparticles should fulfill the following criteria: they should be nontoxic for cells, ie, bioinert or biodegradable; they should effectively carry the molecule of interest, eg, labeling agent or drug; and they should exert their actions specifically on their target, without evoking side effects in other tissues.…”