Relevant Physicochemical Descriptors of “Soft Nanomedicines” to Bypass Biological Barriers

Abstract

Herein, we present an overview on the current status of the characterization techniques and methodologies used to study the physicochemical descriptors that influence the final clinical performance of a given nanomedicine. The described techniques were selected based on their suitability to operate under relevant "native" conditions that mimic the physiological environment. Special emphasis is placed on those techniques that hold a greater potential to unravel dynamic, structural, and compositional features of soft organic nanomedicines relevant to the ability to bypass biological barriers, and hence allow for the rational design of drug delivery platforms with improved biological output.

The past, present, and future of breast cancer models for nanomedicine development

“…Factors present in the unique TMEs can also be considered endogenous stimuli that can aid the rational design of tumor-specific nanomedicines [178] . As an example, we can design nanomedicines with bioresponsive linkers that release their cargo in the presence of microenvironmental factors associated with tumorigenesis, such as acidic pH, elevated ROS, glutathione (GSH), hypoxia, H 2 O 2 , the elevated expression of proteases (including matrix metallopeptidases (MMP) and cathepsins), or other overexpressed proteins [4] , [179] , [180] , [181] . The orthotopic TNBC 4 T1 metastatic model is often employed in the study of polymer-based combination conjugates, where the polymer-drug(s) linker design is a crucial feature ruling final therapeutic output at the primary tumor and metastasis level.…”

“…Lessons learned from those anticancer nanomedicines in current clinical use indicate that a deeper understanding of tumor pathology will dictate not only the incorporation of crucial nanomedicine design features (i.e., responsiveness, size, shape, and targeting moiety choice) [179] but will allow the establishment and implementation of pre-clinical models that provide reliable pharmacological and toxicological data. The foundations for “rational design” should also consider well-recognized aspects that impact the clinical performance of nanomedicines, including tumor vascularization (EPR effect) [269] , the expression of disease-associated cell surface markers that allow cancer cell recognition and uptake, the TME, and the presence infiltrating immune cells at the target site [179] .…”

Polypeptide‐Based Conjugates as Therapeutics: Opportunities and Challenges

“…Interaction of a polypeptide conjugate with the bio‐nano interface is driven by a complex system of simultaneous interactions which requires the step‐wise design of experimental conditions in relevant physiological environments to completely reveal the material's performance in a biological milieu . Polypeptide conjugates are discussed in the following section in relation to the influence of active agent incorporation on the final physico‐chemical properties and the impact on their biological output.…”

“…">2.Lack of scientific data devoted to the strategic and logical design of sophisticated polypeptide systems. 3.Lack of appropriate characterization tools and techniques to disclose the interaction of the nanocarriers with biological interfaces …”

Design of Poly‐l‐Glutamate‐Based Complexes for pDNA Delivery

“…Thus, instead of taking a static stable form, polymers need to change their properties with time and position in order to protect the nucleic acid outside the cell, facilitate the transfer across the endosomal barrier triggered by acidification, and support intracellular release and bioavailability of the nucleic acid in the required cellular compartment. The sum of all these factors points to the implementation of an intricate design strategy …”