Nanomedicine is revolutionizing the treatment of cancer and has achieved unprecedented outcomes over the past decades. The accumulation of Nanoparticles (NPs) in different tumors relies mainly on the Enhanced Permeability and Retention (EPR) effect benefiting from the wide fenestrae of the tumor vasculature and the lack of lymphatic drainage. However, the EPR effect is recognized as a heterogeneous phenomenon resulting in heterogeneous outcomes of clinical trials. Extensive efforts are exerted to enhance the outcomes of nanomedicine in a larger cohort of patients by employing active targeting strategies. However, actively targeted NPs accumulate in tumors by the EPR effect and hence fail to achieve convincing therapeutic outcomes. These obstacles are gradually being removed by improving the understanding of the Tumor Microenvironment (TME) and the mechanistic interaction of the NPs with its different components. In this review, we provide detailed insights into the past concerns of drug targeting, the current trends of TME reengineering, and the future implications for overcoming past hurdles. Strategies explored in this regard included the use of companion diagnostics and the modulation of the protein corona associated with the systemic administration of NPs and their interaction with biological macromolecules.

Background: Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study. Methods: TFs were prepared using the modified scalable heating method. A three-factor, three-level Box–Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell–activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively). Results: The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the “do not eat me” signal — CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix–depleting enzyme, produced detrimental effects. Conclusion: HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.

Assuming that polyethylene glycol (PEG)-conjugated or PEGylated nanocarriers always offer outstanding physicochemical properties and pharmacokinetics profiles when compared to non-PEGylated ones, is not always accurate. For example, drug-loaded PEGylated nanocarriers for the treatment of cancer will not magically escape the reticuloendothelial system (RES) sequestration and clearance, benefit from the enhanced permeability and retention (EPR) effect of the tumor leaky vasculature and preferentially accumulate in the target tissue or cells. This is too good to be true. In this review, several drawbacks of PEGylation will be discussed; for example, how PEGylation can give rise to unfavourable physicochemical characteristics (e. g. particle size and release patterns) and post in vivo administration limitations of the formulated nanocarriers (e. g. limited evasion of RES uptake, development of hypersensitivity reactions, reduced intracellular accumulation and interference with the subcellular processing of nanocarriers necessary to produce the intended pharmacological effect).This review aims at providing better understanding of the pros and cons of PEGylation, encouraging the use of PEGylation with caution, avoiding the assumption that PEGylation will provide all advantages needed to deliver nanocarriers to the target tissue and looking for alternatives to optimize nanocarriers’ utilization especially in the delivery of chemotherapeutic agents for the treatment of different types of cancer. This review comprises a summary of some of the reported literature between 2013 and 2018 using different search engines; PubMed, Science Direct and Google Scholar, and the keywords listed below.

Introduction: Protein corona (PC) deposition on nanoparticles (NPs) in biological systems contributes to a great extent to NPs’ fates; their targeting potential, the interaction with different biological systems and the subsequent functions. PC – when properly tuned – can serve as a potential avenue for optimization of NPs’ use in cancer therapy. Methods: Poly-lactic co-glycolic acid (PLGA)-based NPs exhibiting different physicochemical properties were fabricated and characterized. The PC makeup of these NPs were qualitatively and quantitatively analyzed by Western blot and Bradford assay, respectively. The effect of PC on the release of NPs’ cargos and the intracellular uptake into B16F10 melanoma cells has been studied. Results: The composition of NPs (polymeric PLGA NPs vs lipid-polymer hybrid NPs) and the conjugation of an active targeting ligand (cRGDyk peptide) represented the major determinants of the PC makeup of NPs. The in vitro release of the loaded cargos from the NPs depended on the PC and the presence of serum proteins in the release medium. Higher cumulative release has been recorded in the presence of proteins in the case of peptide conjugated NPs, cNPs, while the unconjugated formulations, uNPs, showed an opposite pattern. NPs intracellular uptake studies revealed important roles of distinct serum and cellular proteins on the extent of NPs’ accumulation in melanoma cells. For example, the abundance of vitronectin (VN) protein from serum has been positively related to the intracellular accumulation of the NPs. Conclusion: Careful engineering of nanocarriers can modulate the recruitment of some proteins suggesting a potential use for achieving endogenous targeting to overcome the current limitations of targeted delivery of chemotherapeutic agents.