2.2.2. Controlled Drug Release

Bearing in mind the complexity, the conventional drug delivery system cannot deliver the chemotherapeutic agents in the most effective concentration to cause tumour cell death, and debilitating side effects occur. This has led to the development of NPs as a drug delivery system (Figure 2), with the aim of achieving tumour specificity and improving the therapeutic index and pharmacokinetic profile of chemotherapeutic agents [18]. Thus, nanotherapy may allow for target active nanosystems containing recognition elements to act or transport and release drugs specifically on affected areas or cells, with the goal of achieving more effective treatment with fewer side effects [1].

Although NPs have been designed to treat various diseases, their most important application has been in cancer. Many of the NPs formulations for cancer treatment have already been approved by regulatory agencies and used in the clinic, but although they produce fewer adverse effects than naked drugs, their therapeutic effectiveness sometimes does not improve substantially. Therefore, the objective is to develop systems with greater therapeutic efficacy [7].

For nanomedicine to have a high therapeutic efficacy in the administration of drugs against cancer, it must comply in the most efficient way with the five steps of the CAPIR cascade: blood Circulation, Accumulation and Penetration in the tumour, cell Internalization and intracellular Release of the drug (CAPIR) [19]. The current approach to nanomedicine development is to adapt the basic physicochemical properties of NPs (size, surface properties and stability, among others) to achieve the CAPIR cascade. As a consequence of the enhanced permeability-retention effect (EPR), it has been proven that passive diffusion allows for tumour localization of nano-chemotherapeutics, but within the TME the localization of nano-chemotherapeutics can be obstructed by different parameters, such as high interstitial fluid pressure, altered extracellular matrix structure, increased cell division or altered lymphatic drainage. Therefore, there is a need to understand the barriers of TME and modulate it to improve the delivery of these drugs [18].

Different types of available NPs are suitable as drug delivery vehicles, which can be passively or actively targeted at tumour tissues to improve the selectivity of these drugs and reduce their side effects. One of the FDA-approved delivery vehicles is liposomes, which are already used in several cancer therapies (i.e., Doxil) [20]. Polymer nanocapsules, which are made of completely hydrophilic polymers, are used to encapsulate hydrophilic drugs. Polymeric micelles are also used for drug delivery, which involves the self-assembly of amphiphilic molecules. The encapsulation of the anti-tumoral drug in these micelles reduces toxicity and improves circulation [7]. An example is the loading of cisplatin into micelles formed by polyethylene glycol (PEG), which increases the time of drug circulation by reducing acute renal accumulation of polymeric micelles [21].

Platinum-derived anti-cancer drugs are of great use, applied in the treatment of cancer, and now a few of them are back in the spotlight because of the recent developments of onco-immunotherapy. In the study conducted by Díez P. et al., a bile-cysplatin acid derivative conjugated to IONPs (iron oxide NPs) was obtained that improves selective cytotoxic activity and promotes the usefulness of IONPs as drug carriers in tumoral cell lines, where platinum derivatives have shown low efficacy. The use of these IONPs may be of great interest in cancer therapies, as they can be designed to bind tumour cells and release the drug in a specific way [22].

Gold-NP, polymer NP or liposomes are also used as carriers of tumour-peptide vaccines that play an important role in tumour immunotherapy [2,23,24]. Chemotherapy based on platinum (II), ruthenium and gold (III) compounds also kills tumour cells [25,26]. One of the most studied gold (III) compounds is the anti-rheumatic drug Auranofin as a cancer treatment [2,27].

Another type of structure involved in nanomedicine are the exosomes, which are naturally occurring nanosized vesicles secreted endogenously by the cells themselves [28]. They are involved in intercellular and tissue-level communication through the transfer of biological material between cells. Exosomes have great potential for use as nano-carriers for various therapies in both inflammatory diseases and cancer, as well as for diagnosis [7].

In general, for controlled drug release, NPs must be designed to escape immune clearance, but they must also be able to adhere to the target tissues and be absorbed or interact with the desired cells in vivo. They can accumulate in the tissues actively or passively, either through transport by intra-organic pressure or through adhesion to specific biological structures in the target tissue by recognition of surface-bound ligands by molecules [29]. In addition to adapting the surface properties of NPs, the optimization of NPs size is also necessary for their accumulation and penetration into tumours and to ensure treatment efficacy [7]. In addition to passive targeting, the active targeting of NPs is also being developed. One example is the design of integrin-targeted nanomedicines using RGD-modified liposomes, which have been shown to result in elevated intracellular levels of doxorubicin [30]. In this sense, novel ligands are being developed against tumour targets, using different targeting biomolecular motifs. There is still discussion about the benefits of active versus passive targeting [31]. Many different controlled release systems are also being developed, which selectively control the rate of drug release by acting on the diseased cells [8].

Another alternative delivery strategy is the combination of multiple antitumour drugs in a single carrier [32]. Co-administration of chemotherapeutic drugs and nucleic acids has led to promising results in overcoming resistance to multiple drugs. Combining therapies against more than one tumour target improves the therapeutic outcome [33]. One of the advantages of nanomedicines is that they can be administered locally, unlike most chemotherapeutics, which are administered systemically.
