The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of 2-hydroxypropyl-β-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of L. donovani. m-DDSLNs (20 mg/kg × 5 days, p.o.) has significantly (P < 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days, p.o.) in L. donovani-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs.

Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death.

Malaria is one of the prevalent tropical diseases caused by the parasitic protozoan of the genus Plasmodium spp. With an estimated 228 million cases, it is a major public health concern with high incidence of morbidity and mortality worldwide. The emergence of drug-resistant parasites, inadequate vector control measures, and the non-availability of effective vaccine(s) against malaria pose a serious challenge to malaria eradication especially in underdeveloped and developing countries. Malaria treatment and control comprehensively relies on chemical compounds, which encompass various complications, including severe toxic effects, emergence of drug resistance, and high cost of therapy. To overcome the clinical failures of anti-malarial chemotherapy, a new drug development is of an immediate need. However, the drug discovery and development process is expensive and time consuming. In such a scenario, nanotechnological strategies may offer promising alternative approach for the treatment and control of malaria, with improved efficacy and safety. Nanotechnology based formulations of existing anti-malarial chemotherapeutic agents prove to exceed the limitations of existing therapies in relation to optimum therapeutic benefits, safety, and cost effectiveness, which indeed advances the patient's compliance in treatment. In this review, the shortcomings of malaria therapeutics and necessity of nanotechnological strategies for treating malaria were discussed.

Visceral Leishmaniasis (VL) has been a major health concern in the developing world, primarily affecting the impoverished people. It is caused by a protozoan parasite Leishmania donovani and is characterized by immune dysfunction that can cause VL patients to succumb to secondary infections. Several adverse side effects limit the current drug options; hence, the need of the hour is some drug options with high efficacy and no toxicity. To make targeted delivery of Amphotericin B, we have used amine-functionalized versions of carbon nanostructures, namely, f-CNT and f-Graphene (f-Grap). The result on f-Grap-AmB because of a much larger surface area was expected to be much better. However, the results on f-Grap-AmB obtained by us showed only marginal improvement (IC50 f-Grap-AmB; 0.0038±0.00119 µg/mL). This is in all likelihood due to the agglomeration effect of f-Grap-AmB, which is invariably obtained with graphene. To resolve this issue, we have synthesized Graphene-CNT composite (Graphene 70% and CNT 30% by weight). Here because CNT is dispersed in between graphene sheets, the agglomeration effect is avoided, and our study suggests that the f-Comp-AmB showed no toxicity against the murine J774A.1 macrophage cell line and did not induce any hepatic or renal toxicity in Swiss albino mice. The f-Comp-AmB also showed a remarkable elevation in the in vitro and in vivo antileishmanial efficacy in comparison to AmB and f-CNT-AmB or f-Grap-AmB in J774A.1 and Golden syrian hamsters respectively. Additionally, we have also observed that the percentage suppression of parasite replication in the spleen of the hamster was significantly higher in the f-Comp-AmB (97.79±0.2375) treated group in comparison with the AmB (85.66±1.164) treated hamster group. To conclude, f-Comp-AmB could be a safe and reliable therapeutic option over the other carbon-based nanoparticles (NPs), i.e., f-CNT-AmB, f-Grap-AmB, and conventional AmB.