Abstract
Abstract 3155
Background:
Multiple myeloma (MM) cells often directly or indirectly induce the formation of osteoclasts, which enhance bone resorption by increasing secretion of a key protease (cathepsin K) to degrade bone matrix, leading to osteolytic lesions and serious skeletal complications. Hence, bone-targeted, osteolytic-responsive therapeutic modalities are greatly needed to improve clinical outcomes for MM.
Methods and Results:
A tri-block copolymer of peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC) has been synthesized as a nanocarrier to improve treatment for MM. The functional peptide with the sequence of CKGHPGGPQAsp8 was designed to possess a bone tropism octapeptide (Asp8), a cathepsin K (CTSK)-cleavable substrate (HPGGPQ), multiple cationic residues and a terminal cysteine for site-specific conjugation. Maleimide-terminated diblock copolymer of PEG-b-PTMC was readily functionalized with the peptide to obtain Pep-b-PEG-b-PTMC that can spontaneously form micelles with the size of 75 nm in diameter. Sixty-six % of polymeric micelles were able to bind to hydroxyl apatite, showing high bone binding capability. The nanoparticles exhibited a negative-to-positive charge conversional profile upon exposure to cathepsin K, an overexpressed enzyme in osteolytic microenvironments. By using doxorubicin as a model drug, Pep-b-PEG-b-PTM showed 7.5 ± 0.5 % and 22.7 ± 1.5% for drug loading content and drug loading efficiency, respectively. More importantly, a unique characteristic of on-demand charge-conversional behaviour in a cathepsin K-rich condition led to enhanced cellular uptake of the nanotherapeutics, as demonstrated by confocal laser scanning microscopy. Enhanced tumor inhibition was observed in 5TGM1 MM cells when nanoparticles were pre-treated with 150 nM cathepsin K, demonstrating enzyme-triggered improved therapy. Efficacy of free DOX or DOX-loaded NPs in 5TGM1 mice bearing myeloma was further preliminarily tested. 5TGM1 mice bearing myeloma were established through injection of 5TGM1 cells (1 × 106 cells in 100 μL PBS) via tail vein, and tumor was allowed to grow for a week before initiating treatment study. Mice (n=3) were injected twice weekly with different therapeutic formulations at equivalent DOX dose (0.75 mg/Kg) or PBS. Tumor burden in the mice was monitored by ELISA measurements of serum IgG2b. Drug-loaded nanoparticles from Pep-b-PEG-b-PTMC were more efficacious in terms of mice survival rate and tumor inhibition when compared to the groups with non-targeted nanoparticles from mPEG-PTMC, free DOX or PBS controls. This improved drug efficacy may be attributed to more selective delivery of DOX to bone metastatic tissues and/or responsiveness of the nanoparticles to cathepsin K, thus improving tumor uptake of DOX, enhancing therapeutic efficacy in terms of tumor reduction as well as MM mouse survival.
Conclusions:
The promising results from this study may prompt the development of bone-targeted, enzyme-triggered drug delivery systems to improve their affinity to skeletal tissues, enhance selectivity for osteolytic regions and improve efficacy of anti-cancer agents, thus facilitating the development of effective nanotherapeutic modalities for multiple myeloma.
Disclosures:
No relevant conflicts of interest to declare.
Preparation andIn VitroEvaluation of a Multifunctional Iron Silicate@Liposome Nanohybrid for pH-Sensitive Doxorubicin Delivery and Photoacoustic Imaging
