While PLGA implants could be beneficial for regenerative
While PLGA implants could be beneficial for regenerative angiogenesis in the context of wound healing, they 3,3',5'-Triiodo-L-thyronine synthesis could also lead to adverse effects. Indeed, extracellular acidification inhibits osteoblast proliferation, differentiation, and extracellular matrix mineralization, which might hamper the use of PLGA/calcium phosphate interference screws in the context of orthopedic surgery .
Future perspectives and challenges – PLGA as therapeutic activity contributor for specific ailments Quite a few published articles reported overall positive therapeutic effects of drug loaded PLGA DDSs but did not incorporate placebo PLGA DDSs as a control group and did not evaluate the potential contributions of lactate/PLGA in the obtained results. Currently there are more than 20 FDA and/or EMA approved PLA/PLGA-based drug products available in different markets . In all these products, PLGA/PLA functions as either drug carrier or supportive structure for the active agent (microspheres and implants). When developing PLGA-based DDSs for sustained local drug release, a potential therapeutic contribution of PLGA/PLA may need to be considered . Once administered, involvement of lactate (released from PLGA) in biological processes may be significant. The intensity of lactate effects depends on whether the released lactate concentration is enough to exert a therapeutic effect or not. A local administration of fast degradable PLGA DDSs could release lactate amounts able to exert a biological activity though avoiding excessive acidification in situ . The total dose of PLGA administered at the site of administration, the PLGA degradation rate, the mechanisms and the capacity of lactate and H+ clearance, and the intrinsic sensitivity of a given tissue to lactate and H+ may be taken into account. New clinical applications and mechanisms of action of PLGA may be discovered if the ongoing researches or clinical studies include a PLGA alone treated group as one of the controls and evaluate the results against the other groups. Deep understanding of lactate released from PLGA involvement in physiological pathways could expand our knowledge in using PLGA DDSs in different treatments. One good example is the use of PLGA DDSs to carry anti-cancer drugs. The angiogenic properties of PLGA DDSs resulting from local delivery of physiologically significant amount of lactate might negatively affect the anti-cancer effects of drugs. Researchers may consider this caveat while formulating PLGA DDSs for local delivery of anti-cancer drugs . On the other side, in diabetic wounds where vasculopathy leads to delayed wound healing, encapsulated drugs in PLGA DDSs could provide a basis for combination therapy (lactate from PLGA and loaded healing agent) in the future .
Acknowledgments The current work is prepared with the support of the Marie Curie Alumni Association (grant number 2018-173).
Introduction As is frequently stated, GPCRs are the largest family of cell surface receptors and are responsible for the signal transduction for a diverse variety of ligands including nucleotides, biogenic amines, peptides and other small molecules (Marchese et al., 1999). GPCRs share a common heptahelical topography and these regions are embedded in the membrane. These seven transmembrane (TM) regions share the most significant levels of receptor identity. As a consequence, the majority of DNA sequences encoding GPCRs were found using methods dependent on sequence homology, mainly PCR or electronic sequence database screening (Marchese et al., 1998). GPCRs activated by similar ligands share the greatest identities with each other. However, newly discovered GPCRs frequently have only distant identities with known GPCRs, and these oGPCRs are difficult to characterize given the diversity in structure of the ligands and effector systems. This problem is compounded as we now realize that many endogenous ligands remain to be discovered. Increasingly, oGPCR characterization has utilized methods of ‘reverse pharmacology’, using the receptor as bait to retrieve ligands from tissue extracts. These efforts have identified endogenous ligands such as apelin, ghrelin, melanin-concentrating hormone, neuromedin U, the orexins, urotensin-II, and UDP-glucose (recently reviewed in Lee et al., 2001a, Civelli et al., 2001, Howard et al., 2001).