Albumin Nanoparticle enhances Oxaliplatin concentration in the Colorectal region to treat Colon Cancer with increased efficacy

doi:10.21203/rs.3.rs-4925423/v1

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Albumin Nanoparticle enhances Oxaliplatin concentration in the Colorectal region to treat Colon Cancer with increased efficacy

https://doi.org/10.21203/rs.3.rs-4925423/v1

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Site specific delivery of anticancer drugs into tumour cells increase therapeutic efficacy while decreasing unwanted side effects. Oxaliplatin (Oxa) is a third-generation platinum derivative used to treat advanced colorectal cancer (CRC). Oxaliplatin loaded bovine serum albumin nanoparticles (Nps-Bsa-Oxa) were formulated by desolvation method. The Nps-Bsa-Oxa were characterized for their size, zeta potential (ZP), surface morphology and charge, in vitro Oxa release, release kinetics, in vitro cytotoxicity, and in vivo studies. The size and surface charge of the Nps-Bsa-Oxa was found to be 163.2 ± 6.3nm and − 27 mV respectively. The Oxa release was studied by dialysis, revealing a biphasic release pattern. In vitro cytotoxicity study was carried out by MTT assay using HT29 cell lines and the Nps-Bsa-Oxa showed higher cytotoxicity when compared with free drug Oxa. In vivo studies on animals revealed that Nps-Bsa-Oxa delivered more Oxa to the colonic region compared to the free form of the drug Oxa.

Colon cancer. Oxaliplatin. Albumin nanoparticles. Colon specific drug delivery. Biodistribution

Colorectal cancer (CRC), despite considerable progress have been made in the early diagnosis and treatment, remains the third most common cancer [1]. As per World Cancer Research Fund International, 1926425 cases were diagnosed in 2022 [2]. The risk factors likely to develop CRC are age (above 50), alcohol consumption, less physical activity, obese conditions, unbalanced diet, inflammatory bowel disease and family history. Histopathological studies have shown that about 95% of colorectal cancer are adenocarcinomas [3]. Approximately one in five patients have metastatic disease and 30–50% develop the same after surgery [4]. Metastasis affects organs like liver, peritoneum, lungs, bone, and brain and also very rarely other organs such as the ovaries and pancreas. An advanced stage of the disease with vascular and/or lymphatic invasion, high concentrations of carcinoembryonic antigen, aggressive cellularity and gene mutations are major risk factors for the metastatic disease [3,5]. If not treated properly, patients diagnosed with metastatic colorectal cancer typically survive for fewer than 8 months. Patients have longer survival period if the number of metastases are limited to a single organ especially liver [3,6]. The treatment options include surgery and chemotherapy. But, chemotherapy remains the main option especially patients with inoperable metastases. The drugs 5-fluorouracil, leucovorin, irinotecan, oxaliplatin and capecitabine are generally used in combination for treatment.

Oxaliplatin (Oxa), chemically trans-1-diaminocyclohexane oxalatoplatin, a third generation platinum derivative used to treat advanced CRC. In physiological fluids, Oxa is converted into active derivatives by nonenzymatic conversion which leads to the formation of various transient reactive species. The reactive species include monoaquo and diaquo 1,2-iaminocyclohexane platinum which bind to macromolecules covalently, and both inter- and intrastrand crosslinks are formed in DNA which interfere with replication of DNA and transcription leading to cell death [7]. Oxa can be used alone, and in combination with other drugs such as 5-FU, irinotecan and raltitrexed. Oxa has been studied in clinical trials to treat other cisplatin resistant cancers such as the gastric, pancreatic, breast, ovarian and lung cancers [8–10]. The therapeutic usefulness is, however, limited owe to its systemic side effects and drug resistance in tumours [11,12]. Oxa also causes acute neuropathy [13]. Further, like other cancerous tissue, in colorectal tumours too the drug distribution is limited and drug concentration may not reach in therapeutic level [13,14]. Hence, many strategies including site specific drug delivery have been developed to overcome these drawbacks.

Site specific drug delivery into different organs/tissues for treating brain diseases and cancer using nano-based carriers is a challenge but fascinates the scientists of this domain [15,16]. Nanoparticles (Nps) have been considered as an advanced and versatile carrier for site specific drug delivery including anticancer drugs [17]. The Nps can alter the biodistribution of entrapped/encapsulated drug, and their size make them able to penetrate across anatomical barriers including the BBB [18–22]. Nps protect the loaded drug from premature degradation and removal from blood. Further, they are get accumulated into tumour cells due to enhanced permeation and retention (EPR) effect. Hence, the therapeutic efficiency of drug can be improved while minimizing side effects. A variety of materials such as synthetic, semisynthetic and natural polymers are used for preparing Nps. Nps prepared with proteins like albumin are nonimmunogenic, biodegradable, biocompatible, and preparation methods are comparatively easy. Both human and bovine serum albumins have been commonly used to prepare Npss. A variety of drug and/or diagnostic molecules can be entrapped into albumin Nps. Drug loaded albumin Nps can be administered by a variety of routes including i.v. route. We have reported a preliminary work [23] and this study was undertaken with the aim to prepare and evaluate Nps-Bsa-Oxa and to explore the efficacy of Nps to deliver the drug into the colonic region.

Oxaliplatin was bought from Sigma-Aldrich, St. Louis, USA. Bovine serum albumin (Bsa) was procured from Roche, USA. The other materials used were analytical/HPLC grade.

2.1 Preparation of Nps-Bsa-Oxa

Desolvation was used to formulate the Nps-Bsa-Oxa [24]. The polymer Bsa and the drug Oxa were dissolved together in a 10 ml solution of 10mM NaCl solution (Table 1). The solution pH was adjusted to a range of 7 to 8. The Nps were formed by adding acetone (desolvating agent), under magnetic stirring, at a flow rate of 1 ml per minute. The addition of acetone was stopped once the turbidity appeared, and 200 µl of gluteraldehyde solution (4% v/v) was added to cross-link and stabilize the formed particles. The cross-linking was continued for another 4h with continuous stirring. Finally, 100 mg anhydrous glucose was added into the nanosuspension, as a cryoprotectant, prior to freeze drying to get powder particles with free-flowing nature. We have formulated five batches by changing the amount of polymer albumin while keeping Oxa quantity as constant (Table 1).

Table 1

Formula for formulating Nps-Bsa-Oxa.
Ingredient	Batch
Ingredient	F-1	F-2	F-3	F-4	F-5
Oxaliplatin	40mg	40mg	40mg	40mg	40mg
Albumin	40mg	80mg	120mg	160mg	200mg
10 mM sodium chloride solution	10ml	10ml	10ml	10ml	10ml
Glutaraldehyde solution (4% v/v) Glucose	200µl 100mg	200µl 100mg	200µl 100mg	200µl 100mg	200µl 100mg

2.2 Nps-Bsa-Oxa characterization

Percentage yield was calculated after lyophilization with respect to the amount of Oxa, Bsa and other solid substances used initially to prepare the Nps. The Nps-Bsa-Oxa (F-1) were analyzed for mean particle diameter using Zetasizer NanoZS (Malvern, UK). The particles were analyzed at 90° angle. The ZP was also measured (F-1) at 25°C using the same instrument. The nanosuspension was subjected to centrifugation (Remi Equipments Ltd., India), to determine the amount of Oxa-loaded into the Nps, at an rpm of 10000 for a period of 20 min. The supernatant, obtained post-centrfugation, was collected and the unbound Oxa present in the supernatant solution was analyzed at 210nm using UV spectroscopy.

2.3 In vitro Oxa release and release kinetics studies

The release of Oxa from the Nps was assessed using the dialysis technique in phosphate buffer at pH 7.4. For this, 5 mg of Oxa equivalent Nps were taken into a dialysis tube and to this small quantity of pH 7.4 phosphate buffer was added. The bag was, then, placed into 100 ml of phosphate buffer (pH 7.4) under stirring with an rpm of 100 at 37°C over a period of 24 h. From the receptor compartment, samples (3 ml) were removed at different time points and fresh buffer (same volume) was added to maintain the sink conditions. Oxa release amount was analyzed at 210nm by UV spectroscopy against blank. The data obtained from the release study (F-1) were used to study the best fit kinetic model and also to find out release mechanism of Oxa from Bsa-Nps. The models used were zero and first order, Higuchi and Korsmeyer-Peppas [25].

2.4 MTT assay

In vitro cytotoxicity of Oxa and Nps-Bsa-Oxa (F-1) was assayed in HT 29 (colon cancer) cell lines by MTT assay [26]. To brief, the cells were cultured in DMEM medium supplemented with 2mM L-glutamine and 10% foetal bovine serum. For screening purpose, approximately 5×10³ cells per well were seeded in 96 well microtitre plates and incubated at 37°C, 95% oxygen, 5% carbon dioxide and 100%RH for a period of 24h. The culture medium was replaced, after 24h, with serum free medium and incubated for 1h after that this was also removed. Following the medium removal, the cells were treated to serum free medium (control well), free Oxa (3.125, 6.25, 12.5, 25 and 50µg/ml) and Nps-Bsa-Oxa equivalent to (3.125, 6.25, 12.5, 25 and 50µg/ml) of Oxa and incubated for 24h. After washing the cells with phosphate buffered saline, 10µl of MTT solution (5mg/ml in PBS) was added to each well and again incubated for additional 4h. After removing the unreacted dye by aspiration, the cells were dissolved in DMSO (100µl/well) and quantitated using ELISA micro plate reader at 570 nm to determine IC₅₀.

2.5 In vivo animal studies

Animal were used to assess the ability of prepared Nps formulation to deliver Oxa into the colonic region. For experiments, adult healthy rats of either sex of Wistar species weighing from 180 to 220g were used. The experimental rats were free to access water and food and placed under a controlled environment with 12h light-dark cycle. The experiments on animals were reviewed and approved by Institutional Animal Ethical Committee. Three groups (six rats/group) were used for experiments. Rats were injected i.v. with Nps-Bsa-Oxa or Oxa solution and the dose level used was 1mg/kg body weight. The rats were sacrificed following injection at predetermined time points like 30min, 1, 2, 4, 8, 12 and 24h. The colonic region was collected immediately and washed with PBS (pH 7.4) and excess fluid was removed before weighing. Phosphate buffer (pH 7.4) was used to homogenize the tissues (20%w/v) followed by centrifugation to obtain clear supernatant, which was collected and kept at -20°C before analysis. The Oxa concentration was estimated using HPLC.

2.6 Statistical analysis

The data are given as mean values ± standard deviation. The significance of difference between the groups was assessed using one-way ANOVA followed by a post hoc Tukey test. A p-value of less than 0.05 was considered statistically significant.

3.1 Preparation of Nps-Bsa-Oxa and drug loading

Desolvation and emulsification are the commonly used methods for preparation of protein Nps [27]. The emulsion method needs organic solvents to remove oily residues and surfactants. Albumin Nps preparation by desolvation involves: (i) the formation of an unstable dispersed system called as coacervates; (ii) hardening of formed coacervates by chemical cross linking; and (iii) purification of formed nanoparticles and lyophilization to obtain powder particles. The particle size and polydispersity index, in this technique, can be controlled by optimizing the formulation parameters [28]. The percentage yield was in the range of 10.29 ± 3.3 to 18.30 ± 1.8w/w, while Oxa loading efficiency of Nps was 8.39 ± 2.3 to 13.86 ± 2.6w/w (Table 2). F-1 showed the highest yield. The Drug loading capacity of any carrier systems which are used for drug delivery/targeting should high enough to reduce the quantity of carrier substance per ml of vehicle at the time of injection. Drug loading efficiency studies revealed that Oxa was successfully entrapped into the albumin Nps. Further, the procedure used was enabled good drug loading into the particles. As shown in Table 2, the loading capacity was 8.39 ± 2.4%w/w for drug polymer ratio 1:1 and gradually increased and attained the maximum of 13.86 ± 2.6w/w for drug polymer ratio 1:3, then decreased as the drug polymer ratio increases.

Table 2

Percentage yield and percentage drug loading of Nps-Bsa-Oxa.
Batch	Percentage yield (w/w)^a	Percentage of drug loading (w/w)^a
F-1	18.30 ± 1.8	8.39 ± 2.4
F-2	13.63 ± 2.7	10.59 ± 1.9
F-3	12.30 ± 3.5	13.86 ± 2.6
F-4	10.66 ± 2.8	12.04 ± 3.4
F-5	10.29 ± 3.3	11.17 ± 1.5

^a (n = 3 ± S.D)

3.2 Particle size and zeta potential

The size of Nps-Bsa-Oxa (F-1) was 329nm and zeta potential (F-1) was − 18.4 ± 3.4mV (Table 3; Fig. 1 and Fig. 2). The size of particles can be modified by adjusting the concentration of albumin, NaCl content and pH, as they influence the albumin molecules’ coagulation. The solution pH plays a vital role, during desolvation, to control albumin molecules’ coagulation. The salts concentration like NaCl influences coagulation of albumin molecules. NaCl protects the charge on the surface of protein molecules by modifying the electrostatic properties [29,30]. Higher concentration of albumin increases the coagulation, because albumin molecules may get more chances for electrostatic and hydrophobic interactions. Hence, increasing in polymer concentration results larger particles. Particles of nanometer range can get easy access in body and transported to different sites through blood circulation. Further, particle size plays an important role to deliver anticancer drugs into the tumour site. For example, LS 174T tumour is a human colon adrenocarcinoma and it was reported that the pore size of the blood capillaries is about 400 nm [31]. Hence, it is obvious that if the particle size is less than 400 nm then they can be taken up by the tumour tissues by passive targeting owing to EPR effect. The size of Nps-Bsa-Oxa (F-1) was 329 nm. Hence, it is believed that the prepared albumin Nps get easy access into the tumour site via the blood capillaries. In addition to particle size, surface charge also plays a role in biodistribution, cellular uptake and removal of Nps. ZP is generally measured to predict the stability of the colloidal system. Higher the charge, more repulsion among the particles which improves easy redisperson and enhance the stability of the Np formulation [32]. The obtained zeta potential value of − 18.4 ± 3.4 mV indicates good stability of albumin Nps.

Table 3

Particle size, zeta potential and release kinetics of Nps-Bsa-Oxa (F-1).
Particle size (in nm)	Zeta potential^a (mV)	Release kinetics
		Zero order r²	First order r²	Higuchi r²	Korsmeyer-Peppas
		Zero order r²	First order r²	Higuchi r²	r²	n
329 nm	– 18.4 ± 3.4	0.9042	0.9609	0.9864	0.9391	0.521

^a(n = 3 ± S.D)

3.3 In vitro Oxa release and release kinetics

The cumulative percentage of Oxa release was varied from 48.84 ± 2.97 to 62.12 ± 2.74 for 24h (Fig. 3) and the results of release kinetics are presented in Table 3. In vitro Oxa release studies showed a time dependent Oxa release from albumin particles (Fig. 3). About 6.15 (F-5) to 9.5% (F-1) w/w of Oxa was released after 30 minutes. This drug release is primarily due to diffusion and desorption from the external surface of the particles. Less Oxa release in the initial phase is desirable as this may reduce release of Oxa from the particles before they reach the site of action (colonic region). The release was steadily increasing in the steady-state phase with about 49 (F-5) to 62 (F-1) %w/w Oxa release after 24 h, which indicates about 51 (F-5) to 38 (F-1) %w/w of Oxa was still entrapped with albumin Nps. The results also revealed that drug release was retarded by increasing albumin concentration. Further, slower drug release in the blood decreases the systemic toxicity of Oxa, as platinum based compounds like carboplatin and Oxa are known for their systemic toxicity [11,12], while increasing the targeting efficiency. The higher r² value of Higuchi (0.9864), obtained for release kinetics, suggests that the release was governed by diffusion. A plot of logarithm of cumulative percentage of Oxa released against the logarithm of time demonstrated a linear relationship (figure not shown) with an r² value of 0.9391. From the slope, the n value was determined and it was 0.521 indicating non-Fickian drug release, which means a combination of diffusion and erosion. Initially, the Oxa release was primarily influenced by diffusion of Oxa through the matrix and Oxa’s partition coefficient between albumin matrix and dissolution media. In the later stages, the Oxa release was owing to the combined effect of diffusion and erosion of albumin matrix.

3.4 MTT Assay

The HT 29 (colon cancer) cells were exposed to various concentration of Oxa ranged between 3.125µg/ml and 50µg/ml. The cell line HT 29 was used for the study was sensitive to Oxa. The IC₅₀ value was 24 µg/ml and 17.5 µg/ml for the free drug and Nps-Bsa-Oxa respectively. It is clear from the IC₅₀ values that the cytotoxic effect of Oxa was higher when it was bound with Nps. The concentration of Oxa needed to inhibit the growth of 50% cells (IC₅₀) was comparatively less in the case of Nps than free Oxa. It has been reported by many authors that Nps bound drug formulations increased the cytotoxicity of drugs when compared with free drug. Poly(alkylcyanoacrylate) Nps containing doxorubicin showed more cytotoxicity on P388 leukaemia cells than free doxorubicin [33]. Nps could be internalized by the process of endocytosis into the cells, hence more drug is delivered intracellularly and the cells become more susceptible for cytotoxic effect [34]. The in vitro cytotoxicity study results showed that Oxa loaded Nps enhanced the cytotoxicity of the Oxa in comparison with free Oxa. Further, the cell line HT 29 showed acceptable Oxa sensitivity.

3.5 In vivo animal studies

Strategies that enhance anticancer effect by increasing drug concentration into tumour cells while minimizing side effects are getting much attention by the researchers. Many Np-based formulations have been studied to transport anti-cancer drugs into tumour cells [35,36]. The available few US-FDA approved products such as Doxil®, Caelyx® and Myocet™ (liposome-based formulations contain the anti-cancer drug doxorubicin), and Abraxane® (Np-based formulation contain the anti-cancer drug paclitaxel) are the fruitful outcome of Np-based anticancer research. Further, it has been reported that the liposomal-based formulations changed the pharmacokinetics and minimized the cardiotoxicity of doxorubicin [37,38]. At the same time, Abraxane® has shown advantages such as solubility improvement and enhanced drug accumulation in tumour cells [39–43]. In the present study, the ability of albumin Nps to deliver more Oxa in the colonic region was studied on rats. The Oxa concentrations (ng/ml) in colonic region, was determined at different time intervals after i.v. injection using Shimadzu LC 2010 HT HPLC (Figs. 4 and 5), are shown in Table 4 and Fig. 6. Both the free Oxa and Nps-Bsa-Oxa was injected separately via the tail vein. The Oxa concentration achieved in the colon for the free Oxa at 0.5, 1, 2, 4, 8. 12 and 24h was 7.9 ± 2.05, 11.47 ± 3.35, 12.23 ± 3.11, 10.79 ± 4.39, 9.82 ± 2.26, 7.74 ± 2.48 and 6.52 ± 1.46ng/ml respectively. For Nps-Bsa-Oxa, it was 14.20 ± 3.9, 23.65 ± 2.75, 25.40 ± 4.67, 20.77 ± 1.90, 16.89 ± 2.06, 11.19 ± 1.88 and 8.98 ± 2.45ng/ml respectively. The results showed both free and Nps-Bsa-Oxa were able to reach the colonic region. In both cases, maximum concentration was achieved after 2h of injection. After 2h, the Oxa concentration in the colon when given as free Oxa and Nps-Bsa-Oxa was 12.23 ± 3.11ng/ml and 25.40 ± 4.67ng/ml respectively and a more than 2-fold increase was observed by Nps. It is important to note that Nps were able to increase the Oxa concentration in all time points. Hence, it is believed that Np-based formulations could be able to transport more drug concentration in the cancerous tissues of colon. Nps, once enter into the systemic circulation, are readily taken up by the macrophages of reticuloendothelial system organs such as liver and spleen. In addition to their size, surface characteristics like charge and hydrophobicity play a pivotal role for opsonization which inturn affect biological fate of particles. Neutral particles have less chance for opsonization when compared to charged particles. Similarly, hydrophilic particles have less opsonization rate in comparison with hydrophobic particles [44]. The higher oxaliplatin delivery into the colonic region may be owing to the hydrophilic nature of albumin. Since albumin is hydrophilic nature, the albumin Nps can avoid opsonization which inturn improve the circulation time in the bloodstream which further increases drug delivery into the colonic region.

Table 4

Oxa concentrations (ng/ml) in colonic region after i.v. injection of free Oxa and Nps-Bsa-Oxa.
Sl. No.	Time (h)	Formulation
Sl. No.	Time (h)	Oxa	Nps-Bsa-Oxa
1	30	7.9 ± 2.05	14.20 ± 3.9^a
2	1	11.47 ± 3.35	23.65 ± 2.75^b
3	2	12.23 ± 3.11	25.40 ± 4.67^a
4	4	10.79 ± 4.39	20.77 ± 1.90^a
5	8	9.82 ± 2.26	16.89 ± 2.06^a
6	12	7.74 ± 2.48	11.19 ± 1.88
7	24	6.52 ± 1.46	8.98 ± 2.45

(n = 6 ± S.D)

^a p < 0.05 Oxa vs. Nps-Bsa-Oxa

^b p < 0.01 Oxa vs. Nps-Bsa-Oxa

Oxa = Oxaliplatin solution; Nps-Bsa-Oxa = Oxaliplatin bound with Nps

In spite of many advances in the diagnosis and therapy, cancer of the colonic region remains the third most common cancer in the world. Insufficient local drug delivery to the tumour cells is one of the major problems that hinder the therapeutic efficacy of many anticancer drugs. Further, the non-specific drug delivery can lead to significant systemic side effects. Nps have been extensively studied to deliver drugs including COVID-19 [45,46]. Further Nps are emerging as an important carrier for the site-specific delivery of drugs into the tumour cells. Nps-based formulations of chemotherapeutic agents have showed an efficient antitumour activity [37,38]. The present study used albumin nanoparticles as a carrier to deliver Oxa into the colonic region. The drug Oxa was successfully loaded into the Nps by desolvation. The in vitro release studies showed a slow and sustained Oxa release pattern. Finally, albumin Nps increased the concentration of drug into the colon when compared with free drug solution. The more Oxa concentration delivered into the colon may be useful to bring new developments in the treatment of colonic cancer. But, further studies are important to consider this as a drug delivery system.

Author contributions B.W., K.M.G., K.D., conceptualized, designed, supervised the work, reviewed and edited the manuscript. J.L.J., K.B.P. and G.S. performed the research work and wrote the first draft.

Ethical Approval The experiments on animals were reviewed and approved by Institutional Animal Ethical Committee (DSCP/RG/RGUHS/IAEC/02/15-16).

Consent to Participate Not applicable.

Competing interest The authors declare no competing interest.

Data availability Data available are from the corresponding author on reasonable request.

Funding The work was supported by a fund by Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India.

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No competing interests reported.

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Albumin Nanoparticle enhances Oxaliplatin concentration in the Colorectal region to treat Colon Cancer with increased efficacy

Status:

Version 1

Abstract

Figures

1 Introduction

2 Materials and Methods

2.1 Preparation of Nps-Bsa-Oxa

2.2 Nps-Bsa-Oxa characterization

2.3 In vitro Oxa release and release kinetics studies

2.4 MTT assay

2.5 In vivo animal studies

2.6 Statistical analysis

3 Results and Discussion

3.1 Preparation of Nps-Bsa-Oxa and drug loading

3.2 Particle size and zeta potential

3.3 In vitro Oxa release and release kinetics

3.4 MTT Assay

3.5 In vivo animal studies

4 Conclusion

Declarations

References

Additional Declarations

Status:

Version 1