The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells. The NME2-associated non-targeted liposome (i.e., without FA8) or pristine NME2 could not up-regulate caspase-8. Caspase-8, an important apoptotic protein involved in the extrinsic pathway of apoptosis-signalling and inhibition of acquired drug resistance, was induced in cancer cells due to the combination treatment of liposomally associated FA8 and NME2 through the activation and subsequent cleavage of RIP-1. Consistently, in a melanoma tumor model too wherein FR is moderately expressed, significant tumour regression was obtained with this liposomal combination of FA8 and NME2. In conclusion, we demonstrate the development of a new FR-targeting ligand molecule whose higher level of inclusion (>10 mol%) in the liposomal formulation altered the mode of anticancer action of the encapsulated drug, thereby indicating a new therapeutic possibility involving FR targeted cancer treatment.

A carbon nanosphere-based dual strategy to target tumor-associated macrophages and tumor cells in glioma lesions within the brain.

Background: Occupational stress can impair one’s health and reduce the efficiency and productivity of work. Delivering health services in rural areas is a tedious job for healthcare workers due to various factors. Inadequate staffing of workers leading to overloaded work and many other factors make them less motivated and experience work stress. Methods: A cross sectional study done in Nelamangla, rural field practice area of BMCRI. A multi stage random sampling technique was applied for the study. 5 PHCs were randomly chosen. Healthcare workers (such as LHV, ANM, Health Assistants, ASHA workers and AWWs) were recruited by probability proportion to sample size. 140 study participants were interviewed using pre tested semi structured questionnaire to collect socio demographic details and work related details; validated professional life stress scale was used to assess stress levels. Descriptive statistics and chi square test were used. Results: 37.1% (52) had mild stress, 52.1% (73) were moderately stressed, 10.7% (15) were severely stressed and none of them were very severely stressed that needed immediate intervention. Working hours, job satisfaction, clarity about work, amount of work exceeding stipulated time, loss of interest at work, not being rewarded and valued for their work are few of the factors that are found to be associated with stress levels. Conclusions: Work related factors have been the main stressors and higher stress levels might impede the performance of the workers and hence addressing this is necessary.

Drug resistance has a major impact on the treatment of several cancers. This is mainly due to the overexpression of cellular drug efflux proteins. Hence, drug‐delivery systems that can avoid this resistance are needed. We report PR10, a progesterone‐cationic lipid conjugate, as a self‐assembling nanoaggregate that delivers a drug cargo of etoposide, a topoisomerase inhibitor, selectively to cancer cells. In this study, we observed that etoposide nanoaggregates (P : E) caused selective and enhanced toxicity in etoposide‐resistant CT26 cancer cells (IC50 9 μM) compared to when etoposide (IC50>20 μM) was used alone. Concurrently, no toxicity was observed in etoposide‐sensitive HEK293 cells for P : E treatment (IC50>20 μM). The P : E‐treated cancer cells seem to have no effect on ABCB1 expression, but etoposide‐treated cells exhibited a twofold increase in ABCB1 expression, a potent efflux protein for several xenobiotic compounds. This observation supports the notion that the enhanced toxicity of P : E nanoaggregates is due to their ability to keep the expression of ABCB1 low, thus allowing longer intracellular residence of etoposide. In a BALB/c orthotopic colorectal cancer model, the nanoaggregates led to enhanced survival (45 days) compared to etoposide‐treated mice (39 days). These findings suggest that PR10 could be used as a potential cancer‐selective etoposide delivery vehicle to treat several etoposide‐resistant cancers with fewer side effects due to the nonspecific toxicity of the drug.

Progesterone (PR) is an endogenous steroid hormone that activates the progesterone receptor (PgR) and is known to play a critical role in cancer progression. Herein, we report the development of cationic lipid-conjugated PR derivatives by covalently conjugating progesterone with cationic lipids of varying hydrocarbon chain lengths (n = 6–18) through a succinate linker. Cytotoxicity studies performed on eight different cancer cell lines reveal that PR10, one of the lead derivatives, exerts notable toxicity (IC50 = 4–12 μM) in cancer cells irrespective of their PgR expression status and remains largely nontoxic to noncancerous cells. Mechanistic studies show that PR10 induces G2/M-phase cell cycle arrest in cancer cells, leading to apoptosis and cell death by inhibiting the PI3K/AKT cell survival pathway and p53 upregulation. Further, in vivo study shows that PR10 treatment significantly reduces melanoma tumor growth and prolongs the overall survival of melanoma tumor-bearing C57BL/6J mice. Interestingly, PR10 readily forms stable self-aggregates of ∼190 nm size in an aqueous environment and exhibits selective uptake into cancerous cell lines. In vitro uptake mechanism studies in various cell lines (cancerous cell lines B16F10, MCF7, PC3, and noncancerous cell line HEK293) using endocytosis inhibition proves that PR10 nanoaggregates enter selectively into the cancer cells predominantly using macropinocytosis and/or caveolae-mediated endocytosis. Overall, this study highlights the development of a self-aggregating cationic derivative of progesterone with anticancer activity, and its cancer cell-selective accumulation in nanoaggregate form holds great potential in the field of targeted drug delivery.

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