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M.A. Ahmed 1 , S.  Correa M.A. Ahmed 1 , S.  Correa

M.A. Ahmed 1 , S. Correa - PowerPoint Presentation

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M.A. Ahmed 1 , S. Correa - PPT Presentation

24 A Barberio 34 and PT Hammond 34 1 Department of NanoEngineering University of California San Diego CA 92093 2 Department of Biological Engineering Massachusetts Institute of Technology MA ID: 758595

cancer drug irinotecan liposomal drug cancer liposomal irinotecan encapsulation pancreatic peak chemotherapy ratio folfirinox regimen oxalipatin buffer hplc formulation

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Slide1

M.A. Ahmed1, S. Correa2,4, A. Barberio3,4, and P.T Hammond3,4

1Department of NanoEngineering, University of California, San Diego, CA 92093 2Department of Biological Engineering, Massachusetts Institute of Technology, MA 021393Department of Chemical Engineering, Massachusetts Institute of Technology, MA 021394Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, MA 02139

1

4

Introduction

Discussion

Pancreatic cancer is considered one of the leading causes of cancer-related mortalities in the United

States. The one-year survival rate for all stages of pancreatic cancer is 20%. In 2017 alone, 43,090 of 53,670 newly diagnosed American patients will die from pancreatic cancer1. The high mortality rate associated with this disease is in part due to the lack proper therapeutic options for patients diagnosed with it. The FDA-approved three-drug chemotherapy regimen FOLFIRINOX, which is composed of OXALIPLATIN/IRINOTECAN/FLUOROURACIL(5-FU) has shown to improve overall patient survival by 4 months compared to GEMCITABINE chemotherapy alone. FOLFIRINOX has also shown to be one of most effective and promising regimens used for advanced metastatic pancreatic cancer patients today. However, significant toxicity is a limiting issue for this multi-drug regimen and only patients with good performance status are candidates to undergo this chemotherapy treatment. Recent developments in liposomal drug delivery systems have shown significant reduction in toxicity and side effects associated with FOLFIRINOX. For this study, a layer-by-layer modified liposomal drug delivery system was chosen for the simultaneous liposomal encapsulation, and systematic delivery of FOLFIRINOX chemotherapy regimen. This goal was achieved by passive encapsulation of OXALIPLATIN/ IRITNOTECAN and FLUOROURACIL(5-FU) in a liposomal formulation composed of DSPC/DSPG/CHOLESTEROL (7:2:1 molar ratio)2.

For future studies CISPLATIN

can be chosen over OXALIPALTIN. Earlier studies by Lippard,et al has shown the possibility of functionalizing CISPLATIN with lipid tails. This approach may enhance the drug encapsulation efficiency for the lipophilic drug CISPLATIN.4 Improvement of liposomal formulation is needed for the incorporation of the functionalizing CISPLATIN with lipid tails.More studies are needed for drug encapsulation efficiency. Further experiments are needed to Determine the optimal drug ratio for drug loading inside the the liposomal complex.

American Cancer Society. (n.d.). Key statistics for Pancreatic Cancer. Retrieved from https://www.cancer.org/cancer/pancreatic-cancer/about/key-statistics.html Tardi, Paul G., et al. "Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo." Biochimica et Biophysica Acta (BBA)-Biomembranes 1768.3 (2007): 678-687.Correa, Santiago, et al. "Nanostructures: Highly Scalable, Closed‐Loop Synthesis of Drug‐Loaded, Layer‐by‐Layer Nanoparticles (Adv. Funct. Mater. 7/2016)." Advanced Functional Materials 26.7 (2016): 990-990.Zheng, Yao-Rong, et al. "Pt (IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery." Journal of the American Chemical Society 136.24 (2014): 8790-8798.

Experimental S

ystem

References

Simultaneous Liposomal Encapsulation of

FOLFIRINOX

Chemotherapy

Regimen

LIPOSMAL FORMUALTION

:

For this study the following lipid were used :

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/ 1,2-dioctadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) (DSPG)/ cholesterol (7:2:1 molar ratio). Organic solvent: chloroform/ methanol/water (5:1:.1)

Following ultrasonication the liposomes were extruded to 100nm in size and the the external liposomal buffer was exchanged for 300 mM sucrose, 20 mM HEPES, 30 mM EDTA pH 7.4 (SHE) using Tangential Flow Filtration System (figure 1 )

Results

Acknowledgment

Drug loading efficacy:

Data obtained from the HPLC were analyzed, and drug encapsulation for each formulation was determined

Passive encapsulation in low cholesterol environment method used in this study showed promising results for 5-FU and IRINOTECAN. It also showed that the OXALIPLATIN can’t be encapsulated efficiently

using.

Further experimental studies are needed to determine the optimal method for the

incorporation of

OXALIPLATIN in the lipid bilayer while still maintaining the FOLFIRINOX chemotherapy regimen ratio.

Future

Work

A.

Figure 2: A

. HPLC-UV Chromatography data for Standard of 0.5mg/ml of OXALIPATIN/IRINOTECAN/5-FU dissolved in 10% Acetonitrile in Water. B. HPLC-UV Chromatography for OXALIPATIN/IRINOTECAN/5-FU (17:36:80; molar ratio) inside the liposome/ copper complex.

Figure 1

: Tangential Flow Filtration System (TFF) is composed of circuit containing a porous membrane filters that drives the liposome sample through it. The generation of a mild pressure gradient drives the exit of the impurities through the porous membrane filter and into a waste reservoir. The SHE buffer is added to the sample feed reservoir at the same rate as filtrate is generated. In this way the volume in the sample reservoir remains constant, but copper gluconate solution is exchanged with the SHE buffer.3

Graphical Representation

Drug Characterization

Drug loading:

The drug formulation chosen for this study was

composed of OXALIPATIN/IRINOTECAN/5-FU in a 17:36:80; molar ratio. The formulation was hydrated with SHE Buffer. The drug solutions and the liposome were incubated separately at 50C for 5 min to equilibrate the temperature . The two solution were then combined, and the drug encapsulation rate was determined using High-performance liquid chromatography (HPLC). Working principle of HPLC is displayed in figured below

B.

OXALIPATIN

Peak

5-FU

Peak

IRINOTECAN

Peak

IRINOTECAN

Peak

OXALIPATIN

Peak

5-FU

Peak

Copper

Gluconate

Complex, 7.4 pH

Outer solvent:

SHE buffer 7.4 pH