Osteotropic Therapy via Targeted Layer‐by‐Layer Nanoparticles

Abstract

Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. Our approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically-used bisphosphonate. Nanoparticles coated with PAA-Alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL can enable surface modification of nanoparticles for tissue-specific targeting and treatment.

Layer‐by‐Layer Coating of Solid Drug Cores: A Versatile Method to Improve Stability, Control Release and Tune Surface Properties

“…Efficient and cell‐specific uptake can be achieved by functionalizing the surface of the particle with an active targeting moiety . Although few approaches have been described for the functionalization of multilayer capsules with high affinity ligands, only two publications have reported the preparation of targeted LbL‐based drug suspensions with enhanced binding to the cell surface or improved cytotoxicity profile compared to the nontargeted versions in preliminary in vitro experiments. However, further tests are required to fully validate the added value of the active targeting in these systems …”

Engineering Layer‐by‐Layer Thin Films for Multiscale and Multidrug Delivery Applications

“…Passive targeting relies on increased vascular permeability in the regions surrounding injured or inflamed tissues, allowing for enhanced immune surveillance [64]. Given that circulating nanoparticles <6-8 nm in HD undergo rapid renal clearance [4,61,62,69] and that nanoparticles >200-250 nm HD are efficiently cleared by the spleen [70,71], systemically administered LbL nanoparticles should be approximately 20-200 nm in HD. 5-12 nm [65,66] in hydrodynamic diameter (HD) to 200-1200 nm HD [67,68].…”

Multistructured Nanogel‐Based Networks Formed from Interfacial Redox Polymerizations for Modulating Small Molecule Release

“…Controlling the composition of the layers can lead to materials with mechanical properties, surface chemistry, and structural gradients that are challenging to produce or unobtainable in single‐component materials . This approach has broad application in biomaterials, from encapsulating cells and biomolecules that modulate the immune response to implantable materials to developing highly customizable nanoparticles for drug delivery where the polymeric layers can modify drug transport properties via electrostatic interactions or conformational changes in the layer upon environmental stimulation . Creating polymeric layers or coatings upon a crosslinked polymer core has been accomplished through sequential photopolymerization of monomer solutions to form multilaminates, as well as through an interfacially mediated redox initiation.…”