Priming the body to receive the therapeutic agent to redefine treatment benefit/risk profile

Abstract

Many therapeutic agents offer a low useful dose (dose responsible for efficacy)/useless dose (dose eliminated or responsible for toxicity) ratio, mainly due to the fact that therapeutic agents must ensure in one single object all the functions required to deliver the treatment, which leads to compromises in their physico-chemical design. Here we introduce the concept of priming the body to receive the treatment by uncorrelating these functions into two distinct objects sequentially administered: a nanoprimer occupying transiently the main pathway responsible for therapeutic agent limited benefit/risk ratio followed by the therapeutic agent. The concept was evaluated for different nature of therapeutic agents: For nanomedicines we designed a liposomal nanoprimer presenting preferential hepatic accumulation without sign of acute toxicity. This nanoprimer was able to increase the blood bioavailability of nanomedicine correlated with a lower hepatic accumulation. Finally this nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 tumor model when compared to the nanomedicine alone. Then, for small molecules we demonstrated the ability of a cytochrome inhibitor loaded nanoprimer to increase efficacy of docetaxel treatment. These results shown that specific nanoprimers could be designed for each family of therapeutic agents to answer to their specific needs.

Impacts of Intralipid on Nanodrug Abraxane Therapy and on the Innate Immune System

“…Co-delivery of appropriate materials with nanomedicines is another approach. For example, the nano-sized inhibitors of hepatic cytochrome P450 3A4 (CYP3A4) serve as a priming agent to block hepatic metabolism specifically following treatment with nanomedicine, which increases the drug bioavailability and prolongs the survival of the xenograft mice 36,37 . Here, we have provided a novel strategy by using an FDA-approved nutritional supplement, Intralipid, to enhance the drug bioavailability ( Fig.…”

Nanobiotechnology medical applications: Overcoming challenges through innovation

“…However, a major challenge to conventional systemic drug delivery is the non-specific uptake of nanomedicines by the reticuloendothelial system (RES), which inhibits payload delivery and imparts toxicity within RES-associated organs, such as the liver, spleen, and kidney (32). In response, there has been a focus on developing nanoprimers that can prepare a patient's body for the subsequent administration of nanomedicines in a manner that will reduce the therapy's risk profile (33). In a recent study, it was demonstrated that the intravenous administration of intralipids one hour prior to therapy was shown to decrease RES uptake, while increasing the nanomedicine's bioavailability (32).…”

“…Advantageously, it is not required that modifications be applied to the payload or its carrier in order to confer this synergism, which makes it translatable to other BNT-based therapies (32). Another similar study utilized a non-toxic liposomal nanoprimer that presented low levels of hepatic accumulation and increased the subsequently administered nanomedicine's systemic bioavailability (33). It was found that by loading cytochrome inhibitor within the nanoprimer, the efficiency of docetaxel treatment significantly increased (33).…”

“…Another similar study utilized a non-toxic liposomal nanoprimer that presented low levels of hepatic accumulation and increased the subsequently administered nanomedicine's systemic bioavailability (33). It was found that by loading cytochrome inhibitor within the nanoprimer, the efficiency of docetaxel treatment significantly increased (33). In both cases, these lipid-based nanoprimers can be modified, through unique functional design, to express efficient priming for a broad range of nano-based therapies (32,33).…”

“…It was found that by loading cytochrome inhibitor within the nanoprimer, the efficiency of docetaxel treatment significantly increased (33). In both cases, these lipid-based nanoprimers can be modified, through unique functional design, to express efficient priming for a broad range of nano-based therapies (32,33).…”