Targeting therapeutics to bone by conjugation with bisphosphonates

Curr Opin Pharmacol. 2018 Jun;40:87-94. doi: 10.1016/j.coph.2018.03.010. Epub 2018 Apr 4.

Abstract

Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alendronate / administration & dosage*
  • Alendronate / adverse effects
  • Alendronate / chemistry
  • Alendronate / pharmacokinetics
  • Animals
  • Bone Diseases / diagnosis
  • Bone Diseases / drug therapy*
  • Bone Diseases / metabolism
  • Bone Diseases / physiopathology
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Bone and Bones / physiopathology
  • Delayed-Action Preparations
  • Diphosphonates / administration & dosage*
  • Diphosphonates / adverse effects
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacokinetics
  • Drug Carriers*
  • Drug Compounding
  • Durapatite / metabolism
  • Humans
  • Prodrugs / administration & dosage*
  • Prodrugs / adverse effects
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Prostaglandins / administration & dosage*
  • Prostaglandins / adverse effects
  • Prostaglandins / chemistry
  • Prostaglandins / pharmacokinetics
  • Receptors, Prostaglandin E, EP4 Subtype / agonists
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism

Substances

  • Delayed-Action Preparations
  • Diphosphonates
  • Drug Carriers
  • PTGER4 protein, human
  • Prodrugs
  • Prostaglandins
  • Receptors, Prostaglandin E, EP4 Subtype
  • Durapatite
  • Alendronate

Grant support