Colorectal cancer (CRC) continues to be a significant global health burden, prompting the need for more effective and targeted therapeutic strategies. Nanoparticle-based drug delivery systems have emerged as a promising approach to address the limitations of conventional chemotherapy, offering enhanced specificity, reduced systemic toxicity, and improved therapeutic outcomes. This paper provides an in-depth review of the current advancements in the application of nanoparticles as vehicles for targeted drug delivery in CRC therapy. It covers a variety of nanoparticle types, including liposomes, polymeric nanoparticles, dendrimers, and mesoporous silica nanoparticles (MSNs), with a focus on their design, functionalization, and mechanisms of action. This review also examines the challenges associated with the clinical translation of these technologies and explores future directions, emphasizing the potential of nanoparticle-based systems to revolutionize CRC treatment.

Background: Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. This study revealed the apoptotic and anti-growth mechanism of VTD, a previously used anti-hypertensive supplement, can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. Methods and Results: An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/−) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. We have previously shown that casein-coated mesoporous silica nanoparticles (MSNs) offer an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of matrix metalloproteinases (MMPs), particularly MMP-7, by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the “Zip Code” mechanism for the local enrichment of VTD at the tumor sites. After in vitro drug release verification, two independent mouse experiments, a xenograft and a splenolepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg). Animal experiments revealed that MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg) slows down the progress of tumors. Mass spectrometry (MS) revealed improved pharmacokinetics (PK) profile as MSN-COOH/VTD/CAS had less VTD accumulation in non-cancerous organs compared to pure VTD. We further improved nanoparticle targeting and drug release by shifting to calcium-based particles (CBPs). The engineered CBPs demonstrated higher drug-releasing performance. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CBPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CBPs for CRC metastatic tumors with excessive extracellular MMP-7. Conclusions: This study introduces a new platform utilizing nanoparticle-based site-specific delivery of a plant-based anti-metastatic molecule, veratridine, with enhanced safety and therapeutic efficacy for the treatment of metastatic CRC.

Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. Nearly 50% of colorectal cancer (CRC) patients develop liver metastases. This shows the pressing need to develop more effective targeted therapies to decrease the high mortality rates associated with metastatic disease. This study revealed the apoptotic and anti-growth mechanism of veratridine (VTD), a previously used anti-hypertensive supplement. VTD can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/-) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. Recently, we reported that the trypsin-triggered release of anti-cancer small molecules from casein-coated mesoporous silica nanoparticles (MSNs) offers an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of MMPs, particularly MMP-7 by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the "Zip Code" mechanism for the local enrichment of VTD at the tumor sites. MMPs, particularly MMP-7, play a crucial role in CRC liver tumor invasion and formation of metastatic lesions due to their ability to degrade extracellular matrix proteins. Under physiological conditions in non-cancerous cells, the extracellular release of MMPs is limited to a low physiological range; therefore, VTD will not be released at normal non-cancer tissues. After in vitro drug release experiments, two independent mouse experiments, a xenograft and a spleno-hepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2mg/kg). The number and size of developed tumor masses revealed that MSN-COOH/VTD/CAS (VTD, 0.2mg/kg) slows down the progress of tumors in both xenograft and CRC liver mouse models. Based on the in vivo results, we decided we could further improve nanoparticle targeting and drug release; hence, we refocused on calcium-based particles. Calcium carbonate microparticles (CCMPs) and calcium carbonate submicroparticles (CCSMPs) demonstrated higher drug-releasing performance compared to silica-based nanoparticles, MSNs. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CCSMPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CCSMPs for CRC metastatic tumors with excessive extracellular MMP-7. The ability of MMP-7 and MMP-9 to release a drug from casein-coated calcium carbonate particles further expands the material platform for the development of targeted gated drug delivery and release using small anti-metastatic molecules. The target delivery strategy offers the dual benefit of enhancing anticancer effects while minimizing potential side effects on healthy cells, maximizing overall therapeutic efficacy.

Plasmonic materials have got wide attention as a potential candidate for light driven catalysis of chemical conversions by harnessing solar energy to reduce the environmental issues generated by fossil fuels-based bulk chemical industries. Toward diluting this crisis, many reported the utilization of plasmonic nanostructured materials in driving industrially important reactions at normal temperature and pressure. However, these chemical conversions often suffer from low yield difficulties, and poor efficiency problems. Also, the mechanism of energy transfer from plasmon to desired molecules is still not properly understood which retards the efforts of scaling them up. Recent endeavors of using SERS to explore the complex mechanisms associated with plasmonic photocatalysis have shown great promises because of the higher sensitivity of the technique. In this article, our aim is to analyze the role of ultrafast SERS in revealing charge transfer as the primary mechanism of photocatalytic reaction of 4-nitrothiophenol to azobenzene-4,4-dithiol and how nanoparticles other than noble metals can also drive this dimerization reaction with similar potential of noble metals. We also intend to investigate why plasmonic heating occurring at metal surface is inadequate to run photocatalytic conversions. A series of analysis has been done in these works using SERS to gather data and understand the mechanisms involved in the processes by pumping plasmonic resonance simultaneously and investigating signals from molecules at various time delays. These results open the door for researchers to consider SERS as a promising technique to uncover the physical and chemical processes involved in plasmon-driven photocatalysis and to advance toward environment friendly and cost-efficient photochemical conversions in future.