Challenges in Development of Nanoparticle-Based Therapeutics

Abstract

In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.

Protein-Functionalized PLGA Nanoparticles of Lamotrigine for Neuropathic Pain Management

“…Further increasing the amount of Tf from 1.0 to 1.5 mg and the Lf density increased from 10.7 to 13.0 μg/mg, the PS increased from 151.0 to 163.5 nm. Also, the conjugation efficiency dropped from 80.3% to 65.0% with an increase in Tf from 1.0 to 1.5 mg. For, intravenous administration, the preferable PS is below 200 nm, and hence considering the size and conjugation efficiency, 1.0 mg of Tf/Lf was considered as optimized amount (42). The conjugation of amino group of the Tf and Lf to the epoxy group was estimated and found to be 10.6 μg Tf/mg NPs and 11.1 Lf/mg NPs, which represents approximately 186 Tf molecules per NP and 185 Lf molecules per NP.…”

Bioengineered yeast-derived vacuoles with enhanced tissue-penetrating ability for targeted cancer therapy

“…However, curtailing vector-associated toxicity is technically challenging. Therefore, biomaterials that are biocompatible, bioresponsive, and biodegradable could be advantageous over synthetic vectors and continue to be actively developed (8,9). To investigate the tumor targeting and therapeutic efficacy of Affi HER2 Vacuole Dox in vivo, we used a HER2-overexpressing NIH3T6.7 cell-based mouse xenograft model (37).…”

“…Such nanomaterial-based drug delivery systems have shown improved therapeutic efficacy with lower unwanted adverse effects compared with conventional chemotherapy, at least in animal models (1)(2)(3)(4)(5). Despite the appreciable success of cancer nanomedicines in preclinical studies, only a few such agents have entered clinical trials, and fewer still have shown promising therapeutic outcomes and advanced to subsequent trial stages (6)(7)(8). Among factors likely to hamper the clinical feasibility of synthetic cancer-targeting nanomaterials are technical challenges involving their pilot scale, cost-effective production, and intrinsic cytotoxicity associated with these materials.…”

“…In addition to these limitations, tumor tissues have formidable physiological barriers, such as a high interstitial pressure and densely entangled ECM. Most synthetic nanomaterials fail to penetrate tumor tissues deeply and localize only in perivascular areas, thereby limiting their therapeutic efficacy (6)(7)(8). To overcome the limitations associated with synthetic nanomedicines, researchers have recently developed biologically derived, nanosized vesicles as novel drug delivery systems (9)(10)(11)(12).…”

Iron sucrose – characteristics, efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas

“…Accordingly, experts from academia, industry and regulatory bodies suggest a stepwise similarity approach that includes appropriate clinical and/or nonclinical studies that evaluate pharmacokinetics, pharmacodynamics and safety/ efficacy of a nonbiological complex drug's follow-on products in relevant patient populations [38,99,102,103]. As long as proof of therapeutic equivalence and similar safety profiles by appropriate studies is missing, interchange and automatic substitution between nonbiological complex drugs and their follow-on products should be discouraged [39].…”