A Way to Fix Bone Fractures Faster?

Purdue University scientists have designed a novel targeted therapeutic agent, known as dasatinib-aspartate₁₀ conjugate or DAC, that promotes the growth of new bones. DAC comprises a targeted peptide linked to dasatinib (a chemotherapy drug). 

When DAC was intravenously injected, femur fracture healing time was reduced by 60%, according to new research presented at the 2018 American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 Meeting.

The researchers report that DAC concentrates at the surface of the fracture – once localized to the fracture site, dasatinib is released from the conjugate – resulting in fast, targeted repair and increased bone density.

DAC and free-dasatinib were subcutaneously administered to individual cohorts of mice possessing a stabilized femoral midshaft fracture. Treatment with DAC reduced the healing process time by approximately half; from 8 weeks to 3–4 weeks.

A 114% increase in bone density was achieved upon daily treatment of DAC, however treatment with DAC on alternate days for a duration of three weeks was equally effective. When the interval was reduced to every four days a measurable decline in potency was observed. 

The association between DAC dose and body-weight change was monitored throughout the course of the study for each cohort. Mice administered a daily dose of DAC took the longest to recover to normal body-weight indicating that there could be mild toxicity. To avoid the apparent toxicity and to maintain the accelerated repair the researchers propose the optimal dosing interval to be every other day (q.o.d). 

The researchers noted that non-targeted (free) dasatinib led to some improvement in rate of healing, however DAC was far superior and ought to have an improved toxicity – due to it being a targeted treatment that acts specifically at the fracture site. 

The team are now investigating the effectiveness of DAC in other fracture types (e.g. long bone and hip fractures, spinal fusions, and craniofacial fractures).

To learn more about the impact of the study we spoke to presenting author, Mingding Wang, Purdue University and Philip Low, Principal Investigator and Presidential Scholar for Drug Discovery, Purdue Institute for Drug Discovery.

Q: Could you expand on the process of designing/ synthesizing DAC?

A: Our overriding objective was to design a drug that would concentrate the healing power of various bone anabolic agents specifically at the fracture site. The drugs we have designed our selectively targeted to the bone fracture surface, avoiding uptake in other organs and tissues of the body. DAC consists of a fracture-targeting peptide (deca-aspartic acid), a hydrolyzable ester linker, and a drug warhead (dasatinib). The deca-aspartic acid was synthesized via standard solid phase peptide chemistry, then attached to dasatinib via an ester bond.

Q: Could you touch on the significance of these findings and any limitations of the study?

A: Over 6 million people suffer from a bone fracture every year in the US alone. Because most of these fractures limit the patient’s activity, with some causing significant morbidity, loss of productivity, and even death, design, synthesis and testing of a targeted fracture healing agent that could minimize these unwanted consequences seemed important (e.g. 25% of hip fracture patients over 65 will die from complications associated with their broken hips). In animal models, DAC reduces the time for fracture healing by 60%. We believe this reduction in healing time may not only reduce patient morbidity and mortality, but could also limit the enormous financial burden imposed on the healthcare system to care for patients suffering serious broken bones. Thus, we foresee a significant need for this type of therapy.

One limitation of our study at the current stage might be the mouse fracture model that we used. Although mice and humans have very similar fracture healing process, there are still some differences that might require adjusting the concentration or frequency of administration of DAC once it is translated into humans. Thus, we are planning to examine the fracture-healing efficacy of DAC in additional animal species before moving DAC into human clinical trials.

Q: With regards to future research could you touch on next steps?

A: In the future, we are going to test the efficacy of DAC in other fracture types, including long bone fractures, hip fractures, nonunion fractures, spinal fusions, stress fractures, and craniofacial fractures. We are also interested in exploring DAC’s efficacy on fracture healing when comorbidities such as diabetes, infections, or smoking exist.

Q: As well as investigating the efficacy of DAC in other fracture types (as mentioned above), are there plans to progress the research from a mouse model to a clinical trial setting for the fracture type (femur) already investigated?

A: Yes, we do plan to confirm the femur fracture-healing efficacy of DAC in additional animal species before conducting IND-enabling studies that would eventually advance DAC to the human clinical trial.

Reference

Bone Fracture-Targeted Dasatinib Conjugate Potently Enhances Fracture Repair In Vivo. Wednesday, Nov. 7, 10:30 a.m. - 11:30 a.m. (EST). 2018 American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 Meeting.