Recent advancements in metastatic colorectal cancer treatment
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In this presentation, the presenter tries to provide an overview of the current established treatment strategies, based on their clinical outcomes as well as their mechanisms, limitations that remain to be overcome, and their future applicability for the treatment of human Colorectal Cancer.
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Recent advancements in metastatic colorectal cancer treatment
- 1. RECENT ADVANCEMENTS IN COLORECTAL CANCER TREATMENT STRATEGIES Golam Iftakhar Khandakar Ph.D. Student Laboratory of molecular pharmacogenomics Department of Pharmaceutical Sciences Kindai University Email: iftakharkhandakar@outlook.com
- 2. Major signaling pathways relevant to cancers July 2019Drugs 79(13
- 3. Mutation status Small GTPases 1:1, 2-27; July/August KRAS, SMAD4 & TP53 mutations are common in CRC and PDAC
- 4. Outline • Introduction Epidemiology Risk factors • Stages of colon cancer • Treatment Strategies • Conclusion
- 5. CRC Epidemiology • Colorectal cancer is the 3rd common cancer worldwide • 4th leading cause of cancer-related death • The global burden of CRC is expected to increase by 60% (>2.2 million new cases/1.1 million deaths) by year 2030 • In Japan 2nd most common cancer (after lung cancer) CA: A Cancer Journal for Clinicians, Volume: 71, Issue: 1, Pages: 7-33, First published: 12 January 2021, DOI: (10.3322/caac.21654) Global patterns and trends in colorectal cancer incidence and mortality. Arnold M. et al. Gut 2016; 0:1-9.
- 6. Pathways to tumorigenesis in CRC BRAF Mutation in Colorectal Cancer
- 7. Colorectal cancer update CA: A Cancer Journal for Clinicians, Volume: 71, Issue: 1, Pages: 7-33, First published: 12 January 2021, DOI: (10.3322/caac.21654)
- 8. Colorectal Cancer Statistics, Japan Source:: Center for Cancer Control and Information Services, National Cancer Center, Japan (https://ganjoho.jp/en/public/statistics/short_pred.html)
- 9. Colorectal Cancer Statistics, Japan Source:: Center for Cancer Control and Information Services, National Cancer Center, Japan (https://ganjoho.jp/en/public/statistics/short_pred.html)
- 10. Risk Factors Clinical Colorectal Cancer, Vol. 15, No. 3,
- 11. Different Stages of Colorectal Cancer Ref: Memorial solan Kettering Cancer Center Stage 0 abnormal cells are found in the mucosa (innermost layer) of the colon wall. These abnormal cells may become cancer and spread. Stage 0 is also called carcinoma in situ.
- 12. Different Stages of Colorectal Cancer Ref: Memorial solan Kettering Cancer Center Stage I colon cancer means that the tumor has spread beyond the inner lining but remains within the colon and has not spread to the lymph nodes. Lymph nodes are small organs that are part of the immune system and act like filters.
- 13. Different Stages of Colorectal Cancer Ref: Memorial solan Kettering Cancer Center Stage II colon cancer extends through the thick outer muscle layer of the colon but has not spread to the lymph nodes.
- 14. Different Stages of Colorectal Cancer Ref: Memorial solan Kettering Cancer Center Stage III colon cancer has spread outside the colon to one or more lymph nodes. spread to the muscle layer of the colon wall.
- 15. Different Stages of Colon Cancer Ref: Memorial solan Kettering Cancer Center Stage IV Cancer may have spread through the colon wall and may have spread to nearby organs or lymph nodes. Cancer has spread to one organ that is not near the colon, such as the liver, lung, or ovary. Cancer has spread to more than one organ that is not near the colon or into the lining of the abdominal wall.
- 16. Survival by tumor grade Stage 0m 30m 60m % Survival % Survival % Survival I 100 96.1 93.2 Ia 100 91 84.7 IIb 100 80.2 72.2 IIIa 100 91.4 83.4 IIIb 100 77.3 64.1 IIIc 100 67.1 52.3 IIId 100 57.3 43 IIIe 100 43.1 26.8 IV 100 17.3 8.1 J Natl Cancer Inst, Volume 96, Issue 19, 6 October 2004, Pages
- 17. Treatment Strategies of CRC Surgery Medical – Chemotherapy – Targeted therapies – Immunotherapy – RNA therapy – Cutting edge-therapy (Using APTAMER)
- 18. Surgery For invasive Carcinoma of the colon stage I,II,III, surgery is the only curative treatment Surgical approach is dedicated by the lesions’ size and location in the colon For stage II and III, there is a risk of residual micro-metastatic disease Adjuvant therapy role: to eradicate the microscopic metastatic disease
- 19. Wilson, P. M. et al. (2014) Standing the test of time: targeting thymidylate biosynthesis in cancer therapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2014.51 5-FU (1962) 5-FU+ Leucovorin (1991) Irinotecan (2000) Capecitabin e (2001) Oxaliplatin (2004) TAS-102 (2015) Historical Development of Chemotherapy in CRC
- 20. Median overall survival of selected regimens N Engl J Med 2005; 352:476- 487
- 21. Development of targeted therapy in CRC 2004 • Cetuximab 2004 • Bevacizumab 2006 • Panitumumab 2012 • ZIV-aflibercept 2015 • Regorafenib 2017 • Ramuclrumab 2018 • Larotrectinib 2020 • Encorafenib EGFR Inhibition VEGF Inhibition NTRK Inhibition BRAF Inhibition Landscape of Current Targeted Therapies for Advanced Colorectal
- 22. Targeted therapies against EGFR in CRC Landscape of Current Targeted Therapies for Advanced Colorectal
- 23. PEAK Study (Phase II) 10.1200/JCO.2013.53.2473 Journal of Clinical Oncology 32, no. 21 (July 20, Bev-mFOLFOX6 Multicenter, Randomization, open label Pan-mFOLFOX6 Patients Criteria age ≥ 18 years histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum with unresectable metastatic disease Patients Characteristics mFOLFOX6 with either panitumumab 6 mg/kg once every 2 weeks or bevacizumab 5 mg/kg once every 2 weeks Treatment 142 patients randomly assigned to panitumumab plus mFOLFOX6 and 143 to bevacizumab plus mFOLFOX6 (N=285) line
- 24. Outcome of PEAK Study 10.1200/JCO.2013.53.2473 Journal of Clinical Oncology 32, no. 21 (July 20, 2014) Overall survival rate comparison
- 25. Outcome of PEAK Study 10.1200/JCO.2013.53.2473 Journal of Clinical Oncology 32, no. 21 (July 20, 2014) Progression free survival comparison
- 26. PLANET-TTD (Phase II) https://doi.org/10.1016/j.ejca.2017.04.0 Pan-FOLFOX4 1:1 Randomization, open label Pan-FOLFIRI Patients Criteria age ≥ 18 years histologically confirmed WT-KRAS (exon 2) mCRC untreated patients multiple (>4 liver metastasis or any liver metastasis longer than 10 cm) Patients Characteristics Pmab (6 mg/kg) was administered with FOLFOX4 or FOLFIRI every 14 ds for 4–8 cycles Treatment 77 patients (38 received Pmab- FOLFOX4 and 39 received Pmab-FOLFIRI) line
- 27. Outcome of PLANET-TTD Study https://doi.org/10.1016/j.ejca.2017.04.0
- 28. Targeted therapies against VEGF in CRC Landscape of Current Targeted Therapies for Advanced Colorectal
- 29. First Bevacizumab data from Phase III trial published in NEJM
- 30. Hurwitz Study (Phase III) Methods • Total Number of patients: 813 (402 received IFL+ Bevacizumab) and others 413 received IFL+Placebo. • Patient received IFL bolus doses and Bevacizumab (5mg per kilogram body weight every 2 weeks) • The median duration of therapy was 27.6 weeks in the group given IFL plus placebo and 40.4 weeks in the group given IFL plus bevacizumab Parameters IFL+Placebo IFL+Bevacizumab Overall Survival (M) 15.6 20.3 PFS (M) 6.2 10.6 OR (%) 34.8 44.8 One year survival rate (%) 63.4 74.3 AE leading to death(%) 2.8 2.6 Thrombolytic Event (%) 16.2 19.4 Grade 3 or 4 Adverse Events (%) 74.0 84.9 Proteinuria(%) 21.7 26.5 Outcome Conclusions Bevacizumab + fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among
- 31. Comparison between Anti-EGFR and Anti-VEGF targeted therapy Cancer Management and Research 2019:11
- 32. Adverse effects of any severity with anti- EGFR and -VEGF therapies Landscape of Current Targeted Therapies for Advanced Colorectal
- 33. Summary of new targeted therapies in mCRC Landscape of Current Targeted Therapies for Advanced Colorectal Cancer
- 34. Immune checkpoint inhibitors in mCRC 201 7 Pembrolizumab Nivolumab Ipilimumab 201 7 201 8 Advances in immunotherapy for colorectal cancer: a review. Therapeutic advances in gastroenterology, 13,
- 35. Mechanism of action of Immune checkpoint inhibitors in mCRC Kalisz KR. Published Online: October 04, 2019 https://doi.org/10.1148/rg.2019190036
- 36. Efficacy of PD-1 Blockade in tumors with Mismatch- Repair Deficiency (KEYNOTE 028 trial) N engl j med 372;26 nejm.org june 25, Patients Criteria Patients with treatment- refractory progressive metastatic cancer were recruited from three centers for this phase 2 study Patients Characteristics Pembrolizumab :10 mg per kilogram weight every 14 days Treatment 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency Study Outcome Parameters Patients with MMR deficient Patients with MMR proficient Immune related objective response rate (%) 40% 0% Immune related Progression free survival rate (%) 78% 11%
- 37. Approved therapies and associated biomarkers in CRC
- 39. • Multi-Drug Resistance (MDR) • Severe side effects • High Specificity • High Potency • Low Toxicity • Undruggable targets Why RNA Based therapies in mCRC? Others Therapy RNA Therapy
- 40. RNA Based therapeutics in CRC Pharmacological Research 152 (2020)
- 41. Mechanism of RNA Based therapies Pharmacological Research 152 (2020)
- 42. RNA-based therapeutics used in the targeted treatment of CRC Pharmacological Research 152 (2020)
- 43. miR-217 suppresses tumor growth and enhances apoptosis in CRC ZHANG et al: miR-217 REGULATES TUMOR GROWTH AND APOPTOSIS A B
- 44. miR-217 is an important regulator of the MAPK1-induced apoptotic pathway. ZHANG et al: miR-217 REGULATES TUMOR GROWTH AND APOPTOSIS Continue…..
- 45. Limitations of RNA therapy Off targets effects SiRNA degrade quickly that’s why clinically not applicable Short half life Length of effects Special drug delivery need to be considered
- 46. RNA therapy delivery strategy single-stranded RNA is prone to nuclease degradation activate immuno-system and is too large in size and negatively charged which is difficult to cross the cell membrane Therefore , Special delivery system to escape from endosomes, which transport extracellular nanoparticles into the cytoplasm Strategie s RNA delivery mediated by: 1. Viral Vectors 2. Non-Viral Vectors
- 47. RNA therapy delivery with viral vector
- 48. RNA therapy delivery with non-viral vector 1. Using Nanoparticles 2. RNA modifications 3. Gene editing
- 49. Aptamer-based drug delivery system in CRC
- 50. Aptamer Technology DNA/RNA oligonucleotides that bind to a specific target with high affinity and specificity Aptamers allow for improved delivery of drugs to tumor cells Control release of drugs intracellularly Reduce Cost Nature Reviews Drug Discovery volume 9, pages537–550
- 51. Application of Aptamer Technology International Journal of Nanomedicine 2020:15 1059–
- 52. Advantages over antibody npj Precision Oncology (2017) 1:37 ; doi:10.1038/s41698-017- 0041-y
- 53. How Aptamers are obtained npj Precision Oncology (2017) 1:37 ; doi:10.1038/s41698-017-
- 54. Aptamer-based bioconjugate system for CRC targeted therapy npj Precision Oncology (2017) 1:37 ; doi:10.1038/s41698-017-
- 55. EpCAM Aptamer downregulated apoptosis inhibitor proteins survivin in CRC Scientific Reports | 7: 5898 | DOI:10.1038/s41598-017-
- 56. Apt-targeted HACSNPs improves the cytotoxicity of an anticancer drug HT-29 CHO IC50=1.43 Apt-targeted nanoparticles had more cytotoxic effect than non- targeted nanoparticles and the IC50 value was significantly decreased. Carbohydrate Polymers, Volume 121,2015,Pages 190-198,ISSN 0144-8617 HACSNPs=hyaluronan/chitosan nanoparticles
- 57. Apt-MSN-DOXs was effectively used in delivering DOX for the therapy of CRC metastasis. Cellular uptake of Ap-MSN- DOX in SW620 cells was significantly higher than that in MSN-DOX. Ap-MSN-DOX was significantly more cytotoxic than MSN-DOX at the same drug concentration X. Xie et al. / European Journal of Pharmaceutical Sciences 83 (2016)
- 58. Apt-MSN-DOX showed higher cell death activity than MSN-DOX in SW620 cell lines X. Xie et al. / European Journal of Pharmaceutical Sciences 83 (2016) Late apoptosis and necrosis of SW620 cells treated with Ap- MSN-DOX significantly higher than MSN- DOX
Editor's Notes
- Lets first overview of the main EGFR and VEGF angiogenic signaling cascades. Upon EGFR dimerisation and autophosphorylation, the RAS/BRAF/MEK and PI3K/PTEN/AKT pathways are induced. Mitogen-activated protein kinase or MAPK pathways are evolutionarily conserved kinase modules that link extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, migration and apoptosis
- Colorectal and pancreatic cancer progression. (A) Colorectal cancer progression and gene mutations. Colonic epithelial cells undergo a histologic transition from normal to malignant state that is driven by specific genetic events including inactivation of tumor suppressors (APC, SMAD4 and TP53) and activation of the KRAS oncogene. The three stages of adenomas represent tumors of increasing size, dysplasia, and villous content. (B) Pancreatic cancer progression and gene mutations. Multiple tumor types arise from the exocrine pancreas, of which greater than 95% are pancreatic ductal adenocarcinoma (PDAC). Activating point mutations in the KRAS gene occur early, inactivation of the p16/INK4A gene occurs at an intermediate stage, and inactivation of the TP53, SMAD4/DPC4 and BRCA2 genes occurs relatively late. Oncogenes are indicated in green text and tumor suppressors in red text.
- Colorectal cancer is the 3rd common cancer worldwide and 4th leading cause of cancer related death. In Japan, it is the 2nd most common cancer.
- The two main separate pathways observed in CRC development and progression are the chromosomal instability pathway (CIN), which accounts for 75% of the cases, and the micro‐satellite instability (MSI) pathway in 25% of the cases. Two processes are observed to contribute towards the MSI pathway: (1) germ-line mutations from Lynch syndrome and (2) sporadic MLH1 methylation from the serrated methylated pathway.
- In Japan the incidence of colon cancer is more in males than females.
- Regarding death statistics, the rate is more in female than male in Japan.
- Several, largely modifiable, environmental lifestyle factors increase colorectal cancer risk, such as smoking, excessive alcohol intake, increased bodyweight, and red and processed meat intake. In addition some hereditary factors are also responsible for increasing colorectal cancer. Furthermore, type 2 diabetes and colorectal cancer share some of the same risk factors (such as obesity and physical inactivity), individuals with type 2 diabetes maintain their increased risk after correcting for these factors.
- Five year survival by American Joint Committee on Cancer sixth edition staging with proposed lymph node (N) stages. An interesting finding of this study is that, with the AJCC sixth edition staging system, stage IIIa disease appears to be associated with a statistically significantly improved survival compared with that of stage IIb disease. This finding may reflect the National Institutes of Health (NIH) 1990 Consensus Conference guidelines for colorectal cancer that recommend adjuvant chemotherapy for stage III colon cancer patients but do not recommend adjuvant chemotherapy for stage II patients.
- The slide shows the median overall survival is more than 20 months when chemotherapy is combined with targeted therapy. When chemotherapy alone or combination of two chemotherapeutic drugs used to treat the colorectal cancer the therapeutic efficacy was found less. (10-16 months).
- Here is the timeline of development of targeted therapies in colon cancer.
- The table showed that the targeted therapies against EGFR in colorectal cancer. Target therapy against EGFR is now a standard of care in RAS wild-type mCRC. Two monoclonal antibodies (mAbs) are approved: cetuximab (human-mouse chimeric mAb) and panitumumab (fully human mAb) as a first line therapy. Among these two, panitumumab combination showed longer PFS and OS benefit than cetuximab combinations.
- PEAK is the first randomized trial to estimate the treatment effect of an anti-EGFR antibody relative to an anti-VEGF for first-line treatment of WT KRAS in mCRC. The randomized phase II PEAK trial compared the efficacy and safety of mFOLFOX6 plus panitumumab with mFOLFOX plus bevacizumab as first-line therapy in RAS wild-type mCRC. The study primary endpoint was met, with panitumumab showing a 3.5- month PFS increase compared with bevacizumab.
- In this analysis, median OS was 41.3 months in the panitumumab arm and 28.9 months in the bevacizumab arm. The OS, 41.3 months is the longest reported median OS for the use of systemic therapies in the treatment of patients with mCRC.
- Here, PFS was 13.0 months in the panitumumab arm and 9.5 months in the bevacizumab arm suggesting that patients in the WT RAS subgroup had improved PFS with panitumumab treatment.
- In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves out-comes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI[folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.
- In patients with WT-KRAS mCRC and LLD ( Liver-limited diseases) , both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS (early tumour shrinkage) > 30% , allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens.
- Targeted therapies against VEGF in colorectal cancer.
- The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo. Bevacizumab + fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with mCRC.
- Primary tumor location and early tumor shrinkage have emerged as new potential prognostic and predictive factors in mCRC. In case of left-sided colorectal cancer median OS and PFS was higher in anti-EGFR + chemotherapy combination than anti-VEGF + chemotherapy combination.
- The main side effects of the anti-EGFR therapies cetuximab and panitumumab are dermatological toxicities, reported in 85–96% of patients. The most common AE is papulopustular skin rash, generally developing over a period of 6 weeks after starting treatment and potentially impacting quality of life and therapy adherence. On the other hand the main anti-VEGF side effects are cardiovascular and kidney problems.
- These are the summary of new targeted therapies in mCRC. Among them only the Neurotrophic tyrosine receptor kinase (NTRK) gene fusions inhibitors (larotrectinib or entrectinib) were approved by FDA. Small molecule inhibitors like larotrectinib or entrectinib targeting TRK proteins and exerts their mechanism of actions.
- Lists of clinical trials Immune checkpoint inhibitors in mCRC.
- Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body . Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells.
- The data from this small phase II trial of pembrolizumab for the treatment of tumors with and tumors without mismatch-repair deficiency support the hypothesis that mismatch repair– deficient tumors are more responsive to PD-1 blockade than are mismatch repair–proficient tumors.
- .
- RNA therapeutics refer to the use of RNAs as therapeutic agents. These consist different classes of RNAs, each of them regulates gene expression or translation through different mechanisms of action. Small interfering RNAs (or short silencing RNAs, siRNA), microRNAs (miRNA), and antisense oligonucleotides (ASO) are the most commonly used RNA therapeutics for silencing gene expression.
- SiRNAs can be either produced from long dsRNAs and hairpin looped RNA catalyzed by a RNase III enzyme Dicer, or artificially synthesized and introduced into the cells by transfection. They are incorporated into other proteins to form RNA-induced silencing complex (RISC), and unwound to single strand siRNAs subsequently. The single strand siRNAs which remain part of RISC find and bind to complementary mRNAs, and induce the mRNAs cleavage. RNA aptamers are single-strand RNA oligonucleotides with various shapes that can bind to targets such as proteins, peptides, and small molecules. Due to their stable three-dimensional shape, the binding to targets has high affinity and specificity.
- These are the lists of RNA based therapies.
- Effect of miR-217 on RKO cell anchorage-dependent growth. The number of apoptotic cells was significantly higher in RKO cells transfected with miR-217, as measured by PI staining and flow cytometry.
- miR-217 is associated with apoptosis progression, with a strong correlation between Bcl-2, Bcl-xl and miR-217 in CRC cells. The MAPK family member MAPK1 regulates apoptosis and proliferation in cancer via the Bcl-2 and Bcl-xl apoptotic signaling pathways. RKO cells expressing miR-217 were stably transfected with full-length MAPK1. MTT assay , colony formation assay demonstrated that upregulation of MAPK1 in RKO cells overexpressing miR-217 reversed the increased apoptosis and suppressed the cell.
- PEG10 (Protein coding gene), cargo RNA and fusogen vectors are transfected into cells. Inside cells, the PEG10 proteins pack the cargo mRNA and assemble into virus-like particles (VLPs) that are secreted to the growth medium in extracellular vesicles. The medium is then collected and the VLPs are isolated by ultracentrifugation. Finally, the target cells are transfected with the VLPs.
- PEG10 (Protein coding gene), cargo RNA and fusogen vectors are transfected into cells. Inside cells, the PEG10 proteins pack the cargo mRNA and assemble into virus-like particles (VLPs) that are secreted to the growth medium in extracellular vesicles. The medium is then collected and the VLPs are isolated by ultracentrifugation. Finally, the target cells are transfected with the VLPs.
- Applications of Aptamer Technology.
- In the antibody therapy against cancer, the antibody molecule is large and difficulty to penetrate into the tumor tissue. Aptamer has a flexible structure and its size is ~25-fold smaller compared with that of monoclonal antibody. Therefore, aptamer is superior to antibody in tumor accumulation and penetration in vitro and in vivo. Compared with antibodies, aptamers possess little to, no immunogenicity, and low toxicity in normal cell in vivo,.
- Schematic representation of specific aptamer selection using cell-SELEX. Cell-SELEX uses living cell as target. Aptamers bind with living cell membrane proteins. The procedure of cell-SELEX includes positive selection and negative selection. The positive selection is ssDNA library incubation with target cells, following the bound sequences are collected. The bound sequences are incubated with negative cell, and the unbound sequences were collected and served as the negative selection. The unbound nucleic acids are used for amplification, sequencing, and cloning. Aptamers are obtained after 10–15 alternate cycles.
- Schematic illustration of aptamer-based bioconjugate system for CRC targeted therapy. EpCAM, MUC-1, and DHX9 proteins serve as biomarkers against aptamer for CRC detection. Chemotherapy drugs loaded onto nanoparticle-aptamer bioconjugate are used for targeted drug delivery
- EpCAM aptamer-guided RNAi effectively silenced survivin. (a) Specificity and efficacy of EpCAM-aptamer guided RNAi in knocking down survivin mRNA. Chimera or negative control chimera were incubated with HT-29 or HEK-2913T cells for 24 hours and the total RNA was extracted for qRT-PCR analysis of survivin mRNA levels. GAPDH was used as an internal control.
- Here MUC-1 binding Apt conjugated to the surface of the nanoparticles for promoting active targeting of the anticancer 5FU. In HT-29 colon cancer cell is MUC-1 overexpressed cells and CHO is a MUC-1 non overexpressed cells. So Apt-targeted nanoparticles had more cytotoxic effect in HT-29 cells but not in CHO cells.
- When incubated with SW620, Ap-MSN-DOX was significantly more cytotoxic than MSN-DOX at the same drug concentration. This is due to the conjugation of aptamers increasing the recognition of nanoparticles by EpCAM over-expression cells. The EpCAM over-expressing cancer cells incubated with Ap-MSN-DOX could intake more DOX than the cells incubated with MSN-DOX. After the recognition of the EpCAM on the surface of SW620 cells, the aptamers on Ap-MSN-DOX will block the activation of EpCAM and inhibit the mRNA expression, which could lead to a strong decrease in proliferation and metabolism in human carcinoma cells.
- Compared with the untargeted drug delivery system, the targeted drug delivery system can be more effective on cell apoptosis under the same drug concentration. The late apoptosis and necrosis of SW620 cells treated with Ap-MSN-DOX were obviously higher than that of SW620 cells treated with MSN-DOX. This phenomenon may be caused by the different drug uptake efficiencies. DOX is a cell-cycle nonspecific anticancer drug; it can inhibit DNA topoisomerases. The topoisomerases are indispensible for DNA replication during the S phase of cell cycle (Wang et al. 2015). This could explain why late apoptosis and necrosis of the cells were increased.