4. Conclusions
This review presents a collection of coupled experimental/computational studies taken from our own experience in the field of self-assembled dendrimers for heparin binding. These studies emphasize both the potentiality played by this hybrid methodology to the design, synthesis and development of possible protamine replacers in biomedical applications, and the obstacles this field has still overcome before these molecules can be translated into nanomedicines available in clinical settings. To date, reliable multiscale molecular simulations may be easier to perform than experiments. Accordingly, the synergist action of computer modeling and dedicated experiments can dramatically help in reducing the time and costs of the pre- and post-development stages of nanomedicines.
Under this perspective, we started the quest for possible protamine antidotes to be used for heparin anticoagulant activity reversal during chirurgical and other medical practices from covalent PAMAM dendrimers. The results from this investigation identified the EDA-core G2 PAMAM dendrimer as the preferred heparin binder both in buffered saline solution and in human plasma. Nonetheless, as a substantially more degradable, less expensive and easier-to produce new molecular entity could be more amenable for successive GMP production, we decided to exploit self-assembly to fabricate biologically-active nanosystems from simple low-molecular-weight building blocks. Efforts in this respect lead us to the design and synthesis of a plethora of amphiphilic dendrons differing in their polar, apolar, or both components. Collectively, the investigation of all these systems led us to gain a wealth of information about the role played by the nature of the dendron components both in their self-assembling structures and characteristics, and in their affinity for heparin in physiologically relevant environment such as 100% human serum, which will be exploited in our future work in this highly challenging sector of current nanomedicine.