Problems to be solved

Drug delivery systems (DDS) are a matter of intensive scientific investigation and technological developments,. DDS are necessary since many active pharmaceutical ingredients (API) to be employed in therapy, diagnostics or vaccination cause:

1. serious side effects when distributed non-specifically and thereby accumulate in healthy and sensitive tissue such as kidney, liver, myocardium, etc.,
2. provoke adverse immune reactions
3. have poor solubility and accordingly low bioavailability, and
4. inefficient targeting.

DDS are designed to overcome these dose and effect limiting restrictions in the use of specific API. Moreover, DDS are developed to optimise the controlled release of API, enable accumulation in the targeted tissue, facilitate endocytosis and the execution of the desired therapeutic or diagnostic effects.

Currently employed or developed DDS are liposomes, polymersomes, micro or nanoparticles, dendrimers, fullerenes, albumin, carbon nanotubes, etc. Among these, liposomes and polymersomes – further on summarized as nanocapsules – are one of the best established DDS.

However, there are several drawbacks that limit the use and benefits of DDS:

Loading versatility: The active loading of a DDS is specific to the API to be encapsulated or attached. However, there are no satisfying methods available yet that allow an efficient encapsulation for a wide class of API such as proteins and other sensitive biomolecules. Sensitive API are vulnerable to degradation by thermal, pH or organic solvent conditions used in existing DDS production and API encapsulation technologies.

Purification: If loading techniques are inefficient for the API to be employed, non encapsulated API have to removed by downstream processing. The high production costs of many API, the often considerable costs of the processing step itself and the loss of API are a major restriction in the use of DDS, even if they could significantly improve targeting and therapeutic results.

Functionalization: Existing production technologies for nanocapsules only produce bilayer shells with identical inner and outer leaflets. However, biological membranes are always composed asymmetrically to enable specific functions of the constituting lipids, proteins and carbohydrates.

Stability in human blood circulation: DDS are often rapidly opsonized by blood proteins of the innate immune system. This leads to destabilization of the nanocapsule shells by formation of the terminal complement protein complex C5b-9, leading to pore formation and premature release of encapsulated API. Moreover, opsonization enhances phagocytosis by macrophages and monocytes resulting in rapid blood clearance without reaching the therapeutic target. These effects can be decreased by covering DDS with polymer layers of e.g. polyethylene glycol (PEG), but still remain an open challenge. The repeated administration of PEG containing DDS leads to an accelerated blood clearance (ABC) in humans and many animal species.

Targeting: therapeutic targets like solid tumours or immune organs as kidney and spleen can be reached by long circulation enabling the so-called enhanced permeability and retention effect. The main challenge to be solved is the controlled release of encapsulated API and enhanced endocytosis into the cytosol of target cells. Unless specific endocytosis mechanisms are activated, DDS are directed to lysosomes where the API is neutralized without the desired therapeutic effect.