Imran Shair Mohammad

Purpose: Systemic immunotherapy is less effective in patients with liver metastases. Immunoembolization could potentially overcome the immunosuppressive tumor microenvironment, but the optimal immunotherapy agent, embolic, and release kinetics are unknown. Methods: A wide range of immunotherapy agents (cytokines, small molecules, and oligonucleotides) were loaded onto various embolics (stabilized lipiodol emulsions, microspheres-in-lipiodol, LC beads, and PLGA microspheres). Drug loading and release kinetics were evaluated in vitro. A pilot study of transarterial immunoembolization was performed in a pig liver tumor model, using extended release lipiodol/CpG-STAT3ASO formulations. CpG-STAT3ASO is a first-in-class dual-function immunotherapy agent that both stimulates the anti-tumor immune response, and counters immunosuppression in immunologically cold tumors. Safety, pharmacokinetics and efficacy were evaluated in pigs. Results: Immunotherapy-loaded embolics released drug with a half-life ranging from days to weeks in vitro, and up to four days in pig liver tumors (depending on the formulation). A stabilized lipiodol emulsion demonstrated 100% burst release (within five minutes after immunoembolization), compared to <1% burst release with microspheres-in-lipiodol. Immunoembolization using lipiodol/CpG-STAT3ASO resulted in decreased size of pig liver tumors, compared to bland embolization. No adverse events were seen, based on clinical, laboratory, and radiographic evaluation, but peritoneal adhesions were observed in association with immunoembolization using microspheres-in-lipiodol. Conclusions: Extended-release immunotherapy-loaded embolics generate sustained intratumoral delivery of immune stimulants. A pilot study of immunoembolization of pig liver tumors showed decreased tumor size, compared to bland embolization, with no autoimmune adverse events.

Intratumoral injection of immune stimulants could potentially reverse the immunosuppressive tumor microenvironment, but the injected drug rapidly washes out into the systemic circulation. This results in systemic toxicity, and reduced efficacy, potentially requiring daily injections to generate an antitumor immune response. To address this problem, we developed an extended-release hydrogel that retains the immunotherapy agent at the injection site, and releases it over several days, even in highly vascular liver tumors. The extended-release hydrogel is a composite material containing drug-loaded microspheres (for sustained, tunable drug release), embedded in a radiopaque cross-linked hydrogel (for local retention). Using these new intratumoral drug carriers, we demonstrate the ability to safely deliver a wide range of different immunotherapy agents (cytokines, oligonucleotides, small molecules) into pig liver tumors, with no acute systemic toxicity. The microsphere gel reduces burst release by 7.8x (compared to microspheres), and increases half-life by > 15x (compared to hydrogel). Thus, the immunotherapy-loaded microsphere gel enables sustained intratumoral delivery of immune stimulants from a single injection, with low systemic toxicity.

The emergence of nanotechnology offers a promising avenue for enhancing cancer treatment outcomes. In this context, biomimetic nanoparticles have emerged as an exciting frontier in the field of biomedicine. These nanoparticles can emulate essential biological functions, drawing from an abundant reservoir of cellular capabilities. This includes engaging in biological binding, precise homing to tumor sites, and interaction with immune cells. These inherent traits endow biomimetic nanoparticles with a suite of intelligent features, including biocompatibility, low immunogenicity, reduced toxicity, immune evasion, prolonged circulation, homotypic binding, enhanced tumor targeting, and the capability of precise delivery. By integrating biologically inspired coatings derived from cell membranes with nanoparticle cores, these carriers become highly versatile vessels for encapsulating a wide array of therapeutic agents. As a result, they are being extensively harnessed for the precise delivery of drugs and genes, underpinning numerous biomedical applications. This discussion delves into the challenges and opportunities presented by biomimetic nanoparticles and offers a comprehensive exploration of their fundamentals and recent breakthroughs, with an eye towards clinical translation. By bridging the gap between scientific innovation and clinical utility, biomimetic nanoparticles hold great promise for advancing the field of cancer treatment.

“Off-targeting” and receptor density expressed at the target sites always compromise the efficacy of the nanoparticle-based drug delivery systems. In this study, we isolated different cell membranes and constructed cell membrane-cloaked biogenic nanoparticles for co-delivery of antitumor paclitaxel (PTX) and multidrug resistance (MDR)-modulator disulfiram (DSF). Consequently, MDR cancer cell membrane (A549/T)-coated hybrid nanoparticles (A549/T CM-HNPs) selectively recognized the source cells and increased the uptake by ninefold via the homotypic binding mechanism. Moreover, the A549/T CM-HNPs sensitized MDR cells to PTX by suppressing P-glycoprotein (P-gp) activity by 3.2-fold and induced effective apoptosis (70%) in homologous A549/T cells. Cell-membrane coating based on the “homotypic binding” is promising in terms of promoting the accumulation of chemotherapeutics in MDR cells and killing them.

Currently, the use of natural compounds obtained from plants tremendously increased due to their promising therapeutic properties. The aim of this study was to formulate a stable emulgel formulation loaded with Cinnamomum tamala (CT) extract. The antioxidant activity of plant extract was determined by DPPH inhibition assay. The extract was successfully loaded into an emulgels using different concentrations of carbopol-940, liquid paraffin, emulsifying agents and preservatives. Preliminary stability study was performed of 17 CT emulgel formulations at accelerated temperature of 50 °C for 2-months. Organoleptic evaluation, centrifugation, globule size, pH, electrical conductivity and rheological studies were performed for a period of 90-days at different temperature including 8, 25, 40 and 40 °C ±75% RH. The CT extract showed promising antioxidant activity of about 81%. On the other hand, the CT loaded emulgel formulation displayed high physical stability at all tested conditions of temperature and time. However, slight decrease in pH and minimum increase in conductivity was observed at 40 and 40 °C±75% RH. The rheological examination of CT emulgel indicated the flow index values of all the samples kept at different temperatures were less than 1, demonstrated non-newtonian and pseudo-plastic nature of CT emulgel. Taken together, the CT emulgel formulation has been evinced to be an excellent addition in the field of topical formulations.