Dataset Information

Diffusion-limited binding explains binary dose response for local arterial and tumour drug delivery.

ABSTRACT:

Background

Local drug delivery has transformed medicine, yet it remains unclear how drug efficacy depends on physicochemical properties and delivery kinetics. Most therapies seek to prolong release, yet recent studies demonstrate sustained clinical benefit following local bolus endovascular delivery.

Objectives

The purpose of the current study was to examine interplay between drug dose, diffusion and binding in determining tissue penetration and effect.

Methods

We introduce a quantitative framework that balances dose, saturable binding and diffusion, and measured the specific binding parameters of drugs to target tissues.

Results

Model reduction techniques augmented by numerical simulations revealed that impact of saturable binding on drug transport and retention is determined by the magnitude of a binding potential, B(p), ratio of binding capacity to product of equilibrium dissociation constant and accessible tissue volume fraction. At low B(p) (< 1), drugs are predominantly free and transport scales linearly with concentration. At high B(p) (> 40), drug transport exhibits threshold dependence on applied surface concentration.

Conclusions

In this paradigm, drugs and antibodies with large B(p) penetrate faster and deeper into tissues when presented at high concentrations. Threshold dependence of tissue transport on applied surface concentration of paclitaxel and rapamycin may explain threshold dose dependence of in vivo biological efficacy of these drugs.

SUBMITTER: Tzafriri AR

PROVIDER: S-EPMC2852623 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Musculoskeletal disorders are a significant burden on the global economy and public health. Advanced drug delivery plays a key role in the musculoskeletal field and holds the promise of enhancing the repair of degenerated and injured musculoskeletal tissues. Ideally, drug delivery should have the ability to directly deliver therapeutic agents to the diseased/injured sites with a desirable drug level over a period of time. Here, we present a mini-review of the current state-of-the-art research associated with local drug delivery and its use for the treatment of musculoskeletal disorders. First, an overview of drug delivery strategies, with a focus on issues related to musculoskeletal pathology, potential therapeutic strategies, conventional and non-conventional drugs, and various delivery systems, is introduced. Then, we highlight recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering techniques), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications. STATEMENT OF SIGNIFICANCE: Three important aspects are highlighted in this manuscript: 1) The advanced musculoskeletal drug delivery is introduced from the aspects ranging from musculoskeletal disorders, potential therapeutic solutions, and various drug delivery systems. 2) The recent advances in the emerging fields of musculoskeletal local drug delivery, involving therapeutic drugs (e.g., genes, small molecule therapeutics, and stem cells), novel delivery vehicles (e.g., 3D printing and tissue engineering technique), and innovative delivery approaches (e.g., multi-drug delivery and smart stimuli-responsive delivery), are highlighted. 3) The challenges and perspectives of future research directions in the development of musculoskeletal local drug delivery are presented.