Inhibitory potential of iRGD peptide-conjugated garcinol-loaded biodegradable nanoparticles in rat colorectal
Brahamacharry Paul1, Raghuvir H Gaonkar2, Debasmita Dutta1
1Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India.
Abstract:
Targeted drug delivery has become attention in chemotherapy during the last decade. The principle of chemotherapy seeks maximum effect to the desired site and the minimum impact to other undesired sites of action. The nanoparticulated drug delivery system progressed a lot in this aspect in the last twenty years. Plant-derived natural products and their semisynthetic analogues boosted chemotherapy through their excellent mechanistic approach to killing cancer cells. Keeping in mind the available molecular targets in colorectal carcinoma (CRC), in this article, we proposed a peptide conjugated novel polymeric nanoparticle to deliver garcinol against colorectal carcinoma. Integrin binding peptide iRGD, sequence c(CRGDKGPDC), has been selected as a targeting moiety, as most CRC overexpress integrins. We encapsulated garcinol in biodegradable polymeric nanoparticle (PLGA)-conjugated with iRGD peptide on the particles' surface, and analyzed its (iRGD-GAR-NP's) in vitro and in vivo antineoplastic potential against CRC in a comparative way with gracinol (GAR) and garcinol-loaded PLGA nanoparticles (GAR-NP). In vitro cellular studies on human CRC cell lines, HCT116 and HT-29, revealed the superior cytotoxic potential of iRGD-GAR-NP over GAR and GAR-NP. The IC50 value on HCT116 cells was reduced by 2.3 times compared to GAR upon the application of iRGD-GAR-NP. At equivalent doses, iRGD-GAR-NP induced higher apoptosis in HCT116 cells and caused blockage of cell cycle at G0/G1 phase of the same. iRGD-GAR-NP increased the apoptotic population of HCT116 cells by 2.5 times compared to GAR. In vivo biodistribution study uncoiled the ability of GAR-NP and iRGD-GAR-NP to accumulate in the colons of dimethyl hydrazine-induced CRC-bearing Sprague-Dawely (SD) rats. In vivo antitumor efficacy study demonstrated the better effect of iRGD-GAR-NP to reduce CRC tumor progression in experimental animals. The survival rate of animals was also increased by 166% in the case of iRGD-GAR-NP compared to CRC-bearing animals received no treatment.
Insights
This study developed a novel peptide-conjugated nanoparticle delivering garcinol to target colorectal cancer (CRC). The new nanoparticle significantly enhanced anti-cancer effects and improved survival rates in preclinical models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Targeted drug delivery is crucial for effective chemotherapy with reduced side effects.
- Nanoparticulated systems have advanced drug delivery over the past two decades.
- Natural products like garcinol show promise in cancer therapy.
Purpose of the Study:
- To develop and evaluate a novel peptide-conjugated nanoparticle for targeted delivery of garcinol against colorectal carcinoma (CRC).
- To compare the in vitro and in vivo antineoplastic potential of the targeted nanoparticle with free garcinol and non-targeted nanoparticles.
Main Methods:
- Encapsulation of garcinol within biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles.
- Conjugation of iRGD peptide, an integrin-binding moiety, to the nanoparticle surface for targeted delivery to CRC.
- In vitro cytotoxicity and cell cycle analysis on human CRC cell lines (HCT116, HT-29).
- In vivo biodistribution and antitumor efficacy studies in a rat model of chemically induced CRC.
Main Results:
- The iRGD-conjugated garcinol nanoparticles (iRGD-GAR-NP) demonstrated superior in vitro cytotoxicity against CRC cells compared to garcinol (GAR) and garcinol-loaded PLGA nanoparticles (GAR-NP), reducing IC50 by 2.3 times.
- iRGD-GAR-NP significantly increased apoptosis (2.5 times) and induced G0/G1 cell cycle arrest in HCT116 cells.
- In vivo studies showed enhanced accumulation of iRGD-GAR-NP in colon tumors and superior reduction in tumor progression.
- Treatment with iRGD-GAR-NP increased the survival rate of tumor-bearing rats by 166% compared to untreated controls.
Conclusions:
- Peptide-conjugated polymeric nanoparticles offer a promising strategy for targeted delivery of garcinol in colorectal cancer therapy.
- iRGD-GAR-NP exhibits enhanced efficacy in reducing tumor growth and improving survival in preclinical CRC models.
- This targeted nanodelivery system holds potential for improving chemotherapy outcomes in colorectal carcinoma.
