Toward the scale-up production of polymeric nanotherapeutics for cancer clinical trials

Abstract

Nanotherapeutics have gained significant attention for the treatment of numerous cancers, primarily because they can accumulate in and/or selectively target tumors leading to improved pharmacodynamics of encapsulated drugs. The flexibility to engineer the nanotherapeutic characteristics including size, morphology, drug release profiles, and surface properties make nanotherapeutics a unique platform for cancer drug formulation. Polymeric nanotherapeutics including micelles and dendrimers represent a large number of formulation strategies developed over the last decade. However, compared to liposomes and lipid-based nanotherapeutics, polymeric nanotherapeutics have had limited clinical translation from the laboratory. One of the key limitations of polymeric nanotherapeutics formulations for clinical translation has been the reproducibility in preparing consistent and homogeneous large-scale batches. In this review, we describe polymeric nanotherapeutics and discuss the most common laboratory and scale-up formulation methods, specifically those proposed for clinical cancer therapies. We also provide an overview of the major challenges and opportunities for scaling polymeric nanotherapeutics to clinical-grade formulations. Finally, we will review the regulatory requirements and challenges in advancing nanotherapeutics to the clinic.

Keywords: Polymeric nanotherapeutics; cancer; clinical translation; commercialization; scale-up.

Figure 1:. An overview of the steps involved in therapeutic nanotherapeutic production.

Taking a nanotherapeutic formulation to the clinical scale requires an initial scale-up process from laboratory-scale production and further development to industrial-scale production without altering the properties. Furthermore, the nanotherapeutics need to be tested for various physiochemical properties and efficacy against cancer models. Storage of the nanotherapeutics also plays a major role in further clinical trials and FDA approval followed by usage in the hospitals.

Figure 2:. Different types of polymeric nanotherapeutics.

Schematic diagrams of four different types of polymeric nanotherapeutics (nanocapsule, nanosphere, dendrimer, and micelles).

Figure 3:. Schematics of different laboratory-based nanotherapeutic synthesis methods.

(A) Emulsion-solvent evaporation, (B) Emulsion-solvent diffusion, (C) Emulsion-salting out, and (D) Nanoprecipitation.

Figure 4:

A general schematic of two most commonly used microfluidic devices.